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Nguyen L, Ajredini R, Guo S, Romano LEL, Tomas RF, Bell LR, Ranum PT, Zu T, Bañez Coronel M, Kelley CP, Redding-Ochoa J, Nizamis E, Melloni A, Connors TR, Gaona A, Thangaraju K, Pletnikova O, Clark HB, Davidson BL, Yachnis AT, Golde TE, Lou X, Wang ET, Renton AE, Goate A, Valdmanis PN, Prokop S, Troncoso JC, Hyman BT, Ranum LPW. CASP8 intronic expansion identified by poly-glycine-arginine pathology increases Alzheimer's disease risk. Proc Natl Acad Sci U S A 2025; 122:e2416885122. [PMID: 39937857 PMCID: PMC11848317 DOI: 10.1073/pnas.2416885122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 12/06/2024] [Indexed: 02/14/2025] Open
Abstract
Alzheimer's disease (AD) affects more than 10% of the population ≥65 y of age, but the underlying biological risks of most AD cases are unclear. We show anti-poly-glycine-arginine (a-polyGR) positive aggregates frequently accumulate in sporadic AD autopsy brains (45/80 cases). We hypothesize that these aggregates are caused by one or more polyGR-encoding repeat expansion mutations. We developed a CRISPR/deactivated-Cas9 enrichment strategy to identify candidate GR-encoding repeat expansion mutations directly from genomic DNA isolated from a-polyGR(+) AD cases. Using this approach, we isolated an interrupted (GGGAGA)n intronic expansion within a SINE-VNTR-Alu element in CASP8 (CASP8-GGGAGAEXP). Immunostaining using a-polyGR and locus-specific C-terminal antibodies demonstrate that the CASP8-GGGAGAEXP expresses hybrid poly(GR)n(GE)n(RE)n proteins that accumulate in CASP8-GGGAGAEXP(+) AD brains. In cells, expression of CASP8-GGGAGAEXP minigenes leads to increased p-Tau (Ser202/Thr205) levels. Consistent with other types of repeat-associated non-AUG (RAN) proteins, poly(GR)n(GE)n(RE)n protein levels are increased by stress. Additionally, levels of these stress-induced proteins are reduced by metformin. Association studies show specific aggregate promoting interrupted CASP8-GGGAGAEXP sequence variants found in ~3.6% of controls and 7.5% AD cases increase AD risk [CASP8-GGGAGA-AD-R1; OR 2.2, 95% CI (1.5185 to 3.1896), P = 3.1 × 10-5]. Cells transfected with a high-risk CASP8-GGGAGA-AD-R1 variant show increased toxicity and increased levels of poly(GR)n(GE)n(RE)n aggregates. Taken together, these data identify polyGR(+) aggregates as a frequent and unexpected type of brain pathology in AD and CASP8-GGGAGA-AD-R1 alleles as a relatively common AD risk factor. Taken together, these data support a model in which CASP8-GGGAGAEXP alleles combined with stress increase AD risk.
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Affiliation(s)
- Lien Nguyen
- Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL32610
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL32610
- Genetics Institute, University of Florida, Gainesville, FL32610
| | - Ramadan Ajredini
- Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL32610
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL32610
| | - Shu Guo
- Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL32610
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL32610
| | - Lisa E. L. Romano
- Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL32610
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL32610
| | - Rodrigo F. Tomas
- Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL32610
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL32610
| | - Logan R. Bell
- Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL32610
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL32610
| | - Paul T. Ranum
- Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA19104
- Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA19104
| | - Tao Zu
- Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL32610
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL32610
| | - Monica Bañez Coronel
- Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL32610
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL32610
| | - Chase P. Kelley
- Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL32610
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL32610
| | - Javier Redding-Ochoa
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD21287
| | - Evangelos Nizamis
- Division of Medical Genetics School of Medicine, University of Washington, Seattle, WA98195
| | - Alexandra Melloni
- Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA02114
| | - Theresa R. Connors
- Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA02114
| | - Angelica Gaona
- Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA02114
| | - Kiruphagaran Thangaraju
- Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL32610
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL32610
| | - Olga Pletnikova
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD21287
| | - H. Brent Clark
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN55455
| | - Beverly L. Davidson
- Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA19104
- Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA19104
| | - Anthony T. Yachnis
- Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL32610
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL32610
| | - Todd E. Golde
- Center for Translation Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL32610
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL32610
- McKnight Brain Institute, University of Florida, Gainesville, FL32610
| | - XiangYang Lou
- Department of Biostatistics, University of Florida, Gainesville, FL32611
| | - Eric T. Wang
- Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL32610
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL32610
- Genetics Institute, University of Florida, Gainesville, FL32610
| | - Alan E. Renton
- Ronald M. Loeb Center for Alzheimer’s Disease, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY10029
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY10029
| | - Alison Goate
- Ronald M. Loeb Center for Alzheimer’s Disease, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY10029
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY10029
| | - Paul N. Valdmanis
- Division of Medical Genetics School of Medicine, University of Washington, Seattle, WA98195
| | - Stefan Prokop
- Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL32610
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL32610
- Center for Translation Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL32610
- McKnight Brain Institute, University of Florida, Gainesville, FL32610
- Department of Neurology, College of Medicine, University of Florida, Gainesville, FL32611
| | - Juan C. Troncoso
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD21287
| | - Bradley T. Hyman
- Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA02114
| | - Laura P. W. Ranum
- Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL32610
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL32610
- Genetics Institute, University of Florida, Gainesville, FL32610
- McKnight Brain Institute, University of Florida, Gainesville, FL32610
- Department of Neurology, College of Medicine, University of Florida, Gainesville, FL32611
- Norman Fixel Institute for Neurological Disease, University of Florida, Gainesville, FL32608
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Nguyen L. Updates on Disease Mechanisms and Therapeutics for Amyotrophic Lateral Sclerosis. Cells 2024; 13:888. [PMID: 38891021 PMCID: PMC11172142 DOI: 10.3390/cells13110888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 05/08/2024] [Accepted: 05/15/2024] [Indexed: 06/20/2024] Open
Abstract
Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a motor neuron disease. In ALS, upper and lower motor neurons in the brain and spinal cord progressively degenerate during the course of the disease, leading to the loss of the voluntary movement of the arms and legs. Since its first description in 1869 by a French neurologist Jean-Martin Charcot, the scientific discoveries on ALS have increased our understanding of ALS genetics, pathology and mechanisms and provided novel therapeutic strategies. The goal of this review article is to provide a comprehensive summary of the recent findings on ALS mechanisms and related therapeutic strategies to the scientific audience. Several highlighted ALS research topics discussed in this article include the 2023 FDA approved drug for SOD1 ALS, the updated C9orf72 GGGGCC repeat-expansion-related mechanisms and therapeutic targets, TDP-43-mediated cryptic splicing and disease markers and diagnostic and therapeutic options offered by these recent discoveries.
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Affiliation(s)
- Lien Nguyen
- Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA;
- Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL 32610, USA
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA
- Genetics Institute, University of Florida, Gainesville, FL 32610, USA
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Shojaie A, Al Khleifat A, Opie-Martin S, Sarraf P, Al-Chalabi A. Non-motor symptoms in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2024; 25:61-66. [PMID: 37798838 PMCID: PMC11090076 DOI: 10.1080/21678421.2023.2263868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 09/19/2023] [Indexed: 10/07/2023]
Abstract
OBJECTIVE While motor symptoms are well-known in ALS, non-motor symptoms are often under-reported and may have a significant impact on quality of life. In this study, we aimed to examine the nature and extent of non-motor symptoms in ALS. METHODS A 20-item questionnaire was developed covering the domains of autonomic function, sleep, pain, gastrointestinal disturbance, and emotional lability, posted online and shared on social media platforms to target people with ALS and controls. RESULTS A total of 1018 responses were received, of which 927 were complete from 506 people with ALS and 421 unaffected individuals. Cold limbs (p 1.66 × 10-36), painful limbs (p 6.14 × 10-28), and urinary urgency (p 4.70 × 10-23) were associated with ALS. People with ALS were more likely to report autonomic symptoms, pain, and psychiatric symptoms than controls (autonomic symptoms B = 0.043, p 6.10 × 10-5, pain domain B = 0.18, p 3.72 × 10-11 and psychiatric domain B = 0.173, p 1.32 × 10-4). CONCLUSIONS Non-motor symptoms in ALS are common. The identification and management of non-motor symptoms should be integrated into routine clinical care for people with ALS. Further research is warranted to investigate the relationship between non-motor symptoms and disease progression, as well as to develop targeted interventions to improve the quality of life for people with ALS.
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Affiliation(s)
- Ali Shojaie
- Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
| | - Ahmad Al Khleifat
- Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
| | - Sarah Opie-Martin
- Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
| | - Payam Sarraf
- Department of Neuromuscular Diseases, Iranian Centre of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran, and
| | - Ammar Al-Chalabi
- Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
- Department of Neurology, King’s College Hospital, London, UK
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Giardina E, Mandich P, Ghidoni R, Ticozzi N, Rossi G, Fenoglio C, Tiziano FD, Esposito F, Capellari S, Nacmias B, Mineri R, Campopiano R, Di Pilla L, Sammarone F, Zampatti S, Peconi C, De Angelis F, Palmieri I, Galandra C, Nicodemo E, Origone P, Gotta F, Ponti C, Nicsanu R, Benussi L, Peverelli S, Ratti A, Ricci M, Di Fede G, Magri S, Serpente M, Lattante S, Domi T, Carrera P, Saltimbanco E, Bagnoli S, Ingannato A, Albanese A, Tagliavini F, Lodi R, Caltagirone C, Gambardella S, Valente EM, Silani V. Distribution of the C9orf72 hexanucleotide repeat expansion in healthy subjects: a multicenter study promoted by the Italian IRCCS network of neuroscience and neurorehabilitation. Front Neurol 2024; 15:1284459. [PMID: 38356886 PMCID: PMC10865370 DOI: 10.3389/fneur.2024.1284459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 01/05/2024] [Indexed: 02/16/2024] Open
Abstract
Introduction High repeat expansion (HRE) alleles in C9orf72 have been linked to both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); ranges for intermediate allelic expansions have not been defined yet, and clinical interpretation of molecular data lacks a defined genotype-phenotype association. In this study, we provide results from a large multicenter epidemiological study reporting the distribution of C9orf72 repeats in healthy elderly from the Italian population. Methods A total of 967 samples were collected from neurologically evaluated healthy individuals over 70 years of age in the 13 institutes participating in the RIN (IRCCS Network of Neuroscience and Neurorehabilitation) based in Italy. All samples were genotyped using the AmplideXPCR/CE C9orf72 Kit (Asuragen, Inc.), using standardized protocols that have been validated through blind proficiency testing. Results All samples carried hexanucleotide G4C2 expansion alleles in the normal range. All samples were characterized by alleles with less than 25 repeats. In particular, 93.7% of samples showed a number of repeats ≤10, 99.9% ≤20 repeats, and 100% ≤25 repeats. Conclusion This study describes the distribution of hexanucleotide G4C2 expansion alleles in an Italian healthy population, providing a definition of alleles associated with the neurological healthy phenotype. Moreover, this study provides an effective model of federation between institutes, highlighting the importance of sharing genomic data and standardizing analysis techniques, promoting translational research. Data derived from the study may improve genetic counseling and future studies on ALS/FTD.
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Affiliation(s)
- Emiliano Giardina
- Genomic Medicine Laboratory UILDM, IRCCS Santa Lucia Foundation, Rome, Italy
- Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy
| | - Paola Mandich
- IRCCS Ospedale Policlinico San Martino – UOC Genetica Medica, Genova, Italy
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, University of Genova, Genova, Italy
| | - Roberta Ghidoni
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Nicola Ticozzi
- Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
- Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, Università degli Studi di Milano, Milan, Italy
| | - Giacomina Rossi
- Unit of Neurology V – Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Chiara Fenoglio
- Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
| | - Francesco Danilo Tiziano
- Section of Genomic Medicine, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
- Unit of Medical Genetics, Department of Laboratory Science and Infectious Diseases, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Federica Esposito
- Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Laboratory of Human Genetics of Neurological Disorders, Division of Neuroscience, Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Sabina Capellari
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
- DIBINEM Università di Bologna, Bologna, Italy
| | - Benedetta Nacmias
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
- IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy
| | - Rossana Mineri
- Laboratory Medicine, Department of Cytogenetics and Molecular Genetics, IRCCS Humanitas Research Hospital, Milan, Italy
| | | | | | | | - Stefania Zampatti
- Genomic Medicine Laboratory UILDM, IRCCS Santa Lucia Foundation, Rome, Italy
| | - Cristina Peconi
- Genomic Medicine Laboratory UILDM, IRCCS Santa Lucia Foundation, Rome, Italy
| | - Flavio De Angelis
- Department of Mental, Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
- Department of Biology, California State University, Northridge, Northridge, CA, United States
| | | | | | | | - Paola Origone
- IRCCS Ospedale Policlinico San Martino – UOC Genetica Medica, Genova, Italy
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, University of Genova, Genova, Italy
| | - Fabio Gotta
- IRCCS Ospedale Policlinico San Martino – UOC Genetica Medica, Genova, Italy
| | - Clarissa Ponti
- IRCCS Ospedale Policlinico San Martino – UOC Genetica Medica, Genova, Italy
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, University of Genova, Genova, Italy
| | - Roland Nicsanu
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Luisa Benussi
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Silvia Peverelli
- Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Antonia Ratti
- Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
- Department of Medical Biotechnology and Molecular Medicine, Università degli Studi di Milano, Milan, Italy
| | - Martina Ricci
- Unit of Neurology V – Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Giuseppe Di Fede
- Unit of Neurology V – Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Stefania Magri
- Unit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Maria Serpente
- Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Serena Lattante
- Section of Genomic Medicine, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
| | - Teuta Domi
- Experimental Neuropathology Unit, Division of Neuroscience, Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Paola Carrera
- Laboratory of Clinical Molecular Biology, Unit of Genomics for Human Disease Diagnosis, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Elisa Saltimbanco
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Silvia Bagnoli
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
- IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy
| | - Assunta Ingannato
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
- IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy
| | - Alberto Albanese
- Department of Neurology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | | | - Raffaele Lodi
- Policlinico S. Orsola-Malpighi, Department of Biomedical and NeuroMotor Sciences (DiBiNeM), University of Bologna, Bologna, Italy
| | - Carlo Caltagirone
- Department of Clinical and Behavioral Neurology, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Stefano Gambardella
- IRCCS Neuromed, Pozzilli, Italy
- Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy
| | - Enza Maria Valente
- IRCCS Mondino Foundation, Pavia, Italy
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Vincenzo Silani
- Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
- Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, Università degli Studi di Milano, Milan, Italy
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Barberio J, Lally C, Kupelian V, Hardiman O, Flanders WD. Estimated Familial Amyotrophic Lateral Sclerosis Proportion: A Literature Review and Meta-analysis. Neurol Genet 2023; 9:e200109. [PMID: 38045991 PMCID: PMC10689005 DOI: 10.1212/nxg.0000000000200109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 09/22/2023] [Indexed: 12/05/2023]
Abstract
Background and Objectives Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder. Familial (fALS) cases are usually reported to constitute 5%-10% of all ALS cases; however, no recent literature review or meta-analysis of this proportion (referred to throughout as "proportion fALS") has been conducted. Our objective was to estimate the proportion fALS by geographic region and to assess the effect of study characteristics on the estimates. Methods A comprehensive literature review was performed to identify all original studies reporting the number of fALS cases in an ALS cohort. The results were stratified by geographic region, study design (case series or population-based), and decade of study publication. Subgroup analyses were conducted according to family history criteria used to define fALS. We report pooled estimates of the proportion fALS from random-effects meta-analyses when >2 studies are available and I2 is < 90%; weighted averages and ranges are otherwise presented. Results The overall pooled proportion fALS based on a total 165 studies was 8% (0%, 71%). The proportion fALS was 9% (0%, 71%) among 107 case series and 5% (4%, 6%) among 58 population-based studies. Among population-based studies, proportion fALS by geographic region was 6% (5%, 7%; N = 37) for Europe, 5% (3%, 7%; N = 5) for Latin America, and 5% (4%, 7%; N = 12) for North America. Criteria used to define fALS were reported by 21 population-based studies (36%), and proportion fALS was 5% (4%, 5%; N = 9) for first-degree relative, 7% (4%, 11%; N = 4) for first or second-degree relative, and 11% (N = 1) for more distant ALS family history. Population-based studies published in the 2000s or earlier generated a lower pooled proportion fALS than studies published in the 2010s or later. Discussion The results suggest that variability in the reported proportion fALS in the literature may be, in part, due to the differences in geography, study design, fALS definition, and decade of case ascertainment. Few studies outside of European ancestral populations were available. The proportion fALS was marginally higher among case series compared with population-based studies, likely because of referral bias. Criteria used to define fALS were largely unreported. Consensus criteria for fALS and additional population-based studies in non-European ancestral populations are needed.
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Affiliation(s)
- Julie Barberio
- From the Epidemiologic Research and Methods LLC (J.B., C.L., W.D.F.); Rollins School of Public Health (J.B., W.D.F.), Emory University, Atlanta, GA; Biogen (V.K.), Cambridge, MA; and Trinity Biomedical Sciences Institute (O.H.), Dublin, Ireland
| | - Cathy Lally
- From the Epidemiologic Research and Methods LLC (J.B., C.L., W.D.F.); Rollins School of Public Health (J.B., W.D.F.), Emory University, Atlanta, GA; Biogen (V.K.), Cambridge, MA; and Trinity Biomedical Sciences Institute (O.H.), Dublin, Ireland
| | - Varant Kupelian
- From the Epidemiologic Research and Methods LLC (J.B., C.L., W.D.F.); Rollins School of Public Health (J.B., W.D.F.), Emory University, Atlanta, GA; Biogen (V.K.), Cambridge, MA; and Trinity Biomedical Sciences Institute (O.H.), Dublin, Ireland
| | - Orla Hardiman
- From the Epidemiologic Research and Methods LLC (J.B., C.L., W.D.F.); Rollins School of Public Health (J.B., W.D.F.), Emory University, Atlanta, GA; Biogen (V.K.), Cambridge, MA; and Trinity Biomedical Sciences Institute (O.H.), Dublin, Ireland
| | - W Dana Flanders
- From the Epidemiologic Research and Methods LLC (J.B., C.L., W.D.F.); Rollins School of Public Health (J.B., W.D.F.), Emory University, Atlanta, GA; Biogen (V.K.), Cambridge, MA; and Trinity Biomedical Sciences Institute (O.H.), Dublin, Ireland
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Waung MW, Ma F, Wheeler AG, Zai CC, So J. The Diagnostic Landscape of Adult Neurogenetic Disorders. BIOLOGY 2023; 12:1459. [PMID: 38132285 PMCID: PMC10740572 DOI: 10.3390/biology12121459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 11/11/2023] [Accepted: 11/16/2023] [Indexed: 12/23/2023]
Abstract
Neurogenetic diseases affect individuals across the lifespan, but accurate diagnosis remains elusive for many patients. Adults with neurogenetic disorders often undergo a long diagnostic odyssey, with multiple specialist evaluations and countless investigations without a satisfactory diagnostic outcome. Reasons for these diagnostic challenges include: (1) clinical features of neurogenetic syndromes are diverse and under-recognized, particularly those of adult-onset, (2) neurogenetic syndromes may manifest with symptoms that span multiple neurological and medical subspecialties, and (3) a positive family history may not be present or readily apparent. Furthermore, there is a large gap in the understanding of how to apply genetic diagnostic tools in adult patients, as most of the published literature focuses on the pediatric population. Despite these challenges, accurate genetic diagnosis is imperative to provide affected individuals and their families guidance on prognosis, recurrence risk, and, for an increasing number of disorders, offer targeted treatment. Here, we provide a framework for recognizing adult neurogenetic syndromes, describe the current diagnostic approach, and highlight studies using next-generation sequencing in different neurological disease cohorts. We also discuss diagnostic pitfalls, barriers to achieving a definitive diagnosis, and emerging technology that may increase the diagnostic yield of testing.
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Affiliation(s)
- Maggie W. Waung
- Division of General Neurology, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158, USA
| | - Fion Ma
- Institute for Human Genetics, University of California San Francisco School of Medicine, San Francisco, CA 94143, USA
| | - Allison G. Wheeler
- Institute for Human Genetics, University of California San Francisco School of Medicine, San Francisco, CA 94143, USA
- Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Clement C. Zai
- Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada
- Department of Psychiatry, Institute of Medical Science, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Joyce So
- Division of Medical Genetics, Department of Pediatrics, University of California, San Francisco, CA 94158, USA
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Kortazar-Zubizarreta I, Manero-Azua A, Afonso-Agüera J, Perez de Nanclares G. C9ORF72 Gene GGGGCC Hexanucleotide Expansion: A High Clinical Variability from Amyotrophic Lateral Sclerosis to Frontotemporal Dementia. J Pers Med 2023; 13:1396. [PMID: 37763163 PMCID: PMC10532825 DOI: 10.3390/jpm13091396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 09/15/2023] [Accepted: 09/16/2023] [Indexed: 09/29/2023] Open
Abstract
The expanded GGGGCC hexanucleotide repeat (HRE) in the non-coding region of the C9ORF72 gene (C9ORF72-HRE) is the most common genetic cause of familial forms of amyotrophic lateral sclerosis (ALS), FTD, and concurrent ALS and FTD (ALS-FTD), in addition to contributing to the sporadic forms of these diseases. Both syndromes overlap not only genetically, but also sharing similar clinical and neuropathological findings, being considered as a spectrum. In this paper we describe the clinical-genetic findings in a Basque family with different manifestations within the spectrum, our difficulties in reaching the diagnosis, and a narrative review, carried out as a consequence, of the main features associated with C9ORF72-HRE. Family members underwent a detailed clinical assessment, neurological examination, and genetic analysis by repeat-primed PCR. We studied 10 relatives of a symptomatic carrier of the C9ORF72-HRE expansion. Two of them presented the expansion in the pathological range, one of them was symptomatic whereas the other one remained asymptomatic at 72 years. Given the great intrafamilial clinical variability of C9ORF72-HRE, the characterization of patients and family members with particular clinical and genetic subgroups within ALS and FTD becomes a bottleneck for medication development, in particular for genetically focused medicines for ALS and FTD.
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Affiliation(s)
- Izaro Kortazar-Zubizarreta
- Department of Neurology, Bioaraba Health Research Institute, Araba University Hospital-Txagorritxu, 01009 Vitoria-Gasteiz, Spain
| | - Africa Manero-Azua
- Molecular (Epi) Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital, 01009 Vitoria-Gasteiz, Spain; (A.M.-A.); (G.P.d.N.)
| | - Juan Afonso-Agüera
- Department of Neurology, Central University Hospital of Asturias, 33006 Oviedo, Spain;
| | - Guiomar Perez de Nanclares
- Molecular (Epi) Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital, 01009 Vitoria-Gasteiz, Spain; (A.M.-A.); (G.P.d.N.)
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8
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Neylan KD, Miller BL. New Approaches to the Treatment of Frontotemporal Dementia. Neurotherapeutics 2023; 20:1055-1065. [PMID: 37157041 PMCID: PMC10457270 DOI: 10.1007/s13311-023-01380-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/14/2023] [Indexed: 05/10/2023] Open
Abstract
Frontotemporal dementia (FTD) comprises a diverse group of clinical neurodegenerative syndromes characterized by progressive changes in behavior, personality, executive function, language, and motor function. Approximately 20% of FTD cases have a known genetic cause. The three most common genetic mutations causing FTD are discussed. Frontotemporal lobar degeneration refers to the heterogeneous group of neuropathology underlying FTD clinical syndromes. While there are no current disease-modifying treatments for FTD, management includes off-label pharmacotherapy and non-pharmacological approaches to target symptoms. The utility of several different drug classes is discussed. Medications used in the treatment of Alzheimer's disease have no benefit in FTD and can worsen neuropsychiatric symptoms. Non-pharmacological approaches to management include lifestyle modifications, speech-, occupational-, and physical therapy, peer and caregiver support, and safety considerations. Recent developments in the understanding of the genetics, pathophysiology, neuropathology, and neuroimmunology underlying FTD clinical syndromes have expanded possibilities for disease-modifying and symptom-targeted treatments. Different pathogenetic mechanisms are targeted in several active clinical trials, opening up exciting possibilities for breakthrough advances in treatment and management of FTD spectrum disorders.
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Affiliation(s)
- Kyra D Neylan
- University of California San Francisco Memory and Aging Center, San Francisco, USA.
| | - Bruce L Miller
- University of California San Francisco Memory and Aging Center, San Francisco, USA
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9
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Van't Spijker HM, Almeida S. How villains are made: The translation of dipeptide repeat proteins in C9ORF72-ALS/FTD. Gene 2023; 858:147167. [PMID: 36621656 PMCID: PMC9928902 DOI: 10.1016/j.gene.2023.147167] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 01/03/2023] [Indexed: 01/07/2023]
Abstract
A hexanucleotide repeat expansion in the C9ORF72 gene is the most common genetic alteration associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These neurodegenerative diseases share genetic, clinical and pathological features. The mutation in C9ORF72 appears to drive pathogenesis through a combination of loss of C9ORF72 normal function and gain of toxic effects due to the repeat expansion, which result in aggregation prone expanded RNAs and dipeptide repeat (DPR) proteins. Studies in cellular and animal models indicate that the DPR proteins are the more toxic species. Thus, a large body of research has focused on identifying the cellular pathways most directly impacted by these toxic proteins, with the goal of characterizing disease pathogenesis and nominating potential targets for therapeutic development. The preventative block of the production of the toxic proteins before they can cause harm is a second strategy of intense focus. Despite the considerable amount of effort dedicated to this prophylactic approach, it is still unclear how the DPR proteins are synthesized from RNAs harboring repeat expansions. In this review, we summarize our current knowledge of the specific protein translation mechanisms shown to account for the synthesis of DPR proteins. We will then discuss how enhanced understanding of the composition of these toxic effectors could help in refining disease mechanisms, and paving the way to identify and design effective prophylactic therapies for C9ORF72 ALS-FTD.
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Affiliation(s)
- Heleen M Van't Spijker
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Sandra Almeida
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
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10
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Udine E, Jain A, van Blitterswijk M. Advances in sequencing technologies for amyotrophic lateral sclerosis research. Mol Neurodegener 2023; 18:4. [PMID: 36635726 PMCID: PMC9838075 DOI: 10.1186/s13024-022-00593-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 12/23/2022] [Indexed: 01/14/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is caused by upper and lower motor neuron loss and has a fairly rapid disease progression, leading to fatality in an average of 2-5 years after symptom onset. Numerous genes have been implicated in this disease; however, many cases remain unexplained. Several technologies are being used to identify regions of interest and investigate candidate genes. Initial approaches to detect ALS genes include, among others, linkage analysis, Sanger sequencing, and genome-wide association studies. More recently, next-generation sequencing methods, such as whole-exome and whole-genome sequencing, have been introduced. While those methods have been particularly useful in discovering new ALS-linked genes, methodological advances are becoming increasingly important, especially given the complex genetics of ALS. Novel sequencing technologies, like long-read sequencing, are beginning to be used to uncover the contribution of repeat expansions and other types of structural variation, which may help explain missing heritability in ALS. In this review, we discuss how popular and/or upcoming methods are being used to discover ALS genes, highlighting emerging long-read sequencing platforms and their role in aiding our understanding of this challenging disease.
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Affiliation(s)
- Evan Udine
- grid.417467.70000 0004 0443 9942Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL 32224 USA ,grid.417467.70000 0004 0443 9942Mayo Clinic Graduate School of Biomedical Sciences, 4500 San Pablo Road S, Jacksonville, FL 32224 USA
| | - Angita Jain
- grid.417467.70000 0004 0443 9942Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL 32224 USA ,grid.417467.70000 0004 0443 9942Mayo Clinic Graduate School of Biomedical Sciences, 4500 San Pablo Road S, Jacksonville, FL 32224 USA ,grid.417467.70000 0004 0443 9942Center for Clinical and Translational Sciences, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL 32224 USA
| | - Marka van Blitterswijk
- Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL, 32224, USA.
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11
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Che XQ, Lin GZ, Liu XH, Wang G, Zhao QH, Ren RJ. Genetic and Neuroimaging Analysis of SIGMAR1 for Frontotemporal Dementia. J Alzheimers Dis 2023; 95:469-475. [PMID: 37545231 DOI: 10.3233/jad-221195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/08/2023]
Abstract
BACKGROUND Recently, Sigma nonopioid intracellular receptor 1 (SIGMAR1) variants have been shown harboring C9orf72 pathogenic repeat expansions in some frontotemporal dementia (FTD) cases. However, no SIGMAR1 genotype analysis has been reported in a cohort absent of C9orf72 pathogenic repeat expansions to date. OBJECTIVE The present study investigated the contribution of SIGMAR1 independent of C9orf72 gene status to FTD spectrum syndromes. METHODS We directly sequencing the entire coding region and a minimum of 50 bp from each of the flanking introns of SIGMAR1 gene in 82 sporadic FTD patients (female: male = 42 : 40) and 417 controls. For the patient carrying SIGMAR1 variant, a follow-up 3T MR imaging was performed in the study. RESULTS Gene sequencing of SIGMAR1 revealed a rare 3'UTR nucleotide variation rs192856872 in a male patient with semantic dementia independent of C9orf72 gene status. The MR imaging showed asymmetrical atrophy in the anterior temporal lobes and the degeneration extends caudally into the posterior temporal lobes as the disease progresses. ESEFinder analysis showed new SRSF1 and SRSF1-IgM-BRCA1 binding sites with significant scores, which is predicted to affect normal splicing. CONCLUSION We found a novel SIGMAR1 variant independent of C9orf72 gene status associated with semantic dementia phenotype.
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Affiliation(s)
- Xiang-Qian Che
- Department of Neurology & Neuroscience Institute, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guo-Zhen Lin
- Department of Psychiatry, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Hong Liu
- Department of Neurology, Shanghai Putuo District People's Hospital, Shanghai, China
| | - Gang Wang
- Department of Neurology & Neuroscience Institute, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qian-Hua Zhao
- Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
- MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
| | - Ru-Jing Ren
- Department of Neurology & Neuroscience Institute, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Lopez-Herdoiza MB, Bauché S, Wilmet B, Le Duigou C, Roussel D, Frah M, Béal J, Devely G, Boluda S, Frick P, Bouteiller D, Dussaud S, Guillabert P, Dalle C, Dumont M, Camuzat A, Saracino D, Barbier M, Bruneteau G, Ravassard P, Neumann M, Nicole S, Le Ber I, Brice A, Latouche M. C9ORF72 knockdown triggers FTD-like symptoms and cell pathology in mice. Front Cell Neurosci 2023; 17:1155929. [PMID: 37138765 PMCID: PMC10149765 DOI: 10.3389/fncel.2023.1155929] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 03/27/2023] [Indexed: 05/05/2023] Open
Abstract
The GGGGCC intronic repeat expansion within C9ORF72 is the most common genetic cause of ALS and FTD. This mutation results in toxic gain of function through accumulation of expanded RNA foci and aggregation of abnormally translated dipeptide repeat proteins, as well as loss of function due to impaired transcription of C9ORF72. A number of in vivo and in vitro models of gain and loss of function effects have suggested that both mechanisms synergize to cause the disease. However, the contribution of the loss of function mechanism remains poorly understood. We have generated C9ORF72 knockdown mice to mimic C9-FTD/ALS patients haploinsufficiency and investigate the role of this loss of function in the pathogenesis. We found that decreasing C9ORF72 leads to anomalies of the autophagy/lysosomal pathway, cytoplasmic accumulation of TDP-43 and decreased synaptic density in the cortex. Knockdown mice also developed FTD-like behavioral deficits and mild motor phenotypes at a later stage. These findings show that C9ORF72 partial loss of function contributes to the damaging events leading to C9-FTD/ALS.
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Affiliation(s)
| | - Stephanie Bauché
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
| | - Baptiste Wilmet
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
| | - Caroline Le Duigou
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
| | - Delphine Roussel
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
| | - Magali Frah
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
| | - Jonas Béal
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
| | - Gabin Devely
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
| | - Susana Boluda
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
| | - Petra Frick
- German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
| | | | - Sébastien Dussaud
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
| | - Pierre Guillabert
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
| | - Carine Dalle
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
| | - Magali Dumont
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
| | - Agnes Camuzat
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
| | - Dario Saracino
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
| | - Mathieu Barbier
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
| | - Gaelle Bruneteau
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
| | | | - Manuela Neumann
- German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
- Department of Neuropathology, Tübingen University Hospital, Tübingen, Germany
| | - Sophie Nicole
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
| | - Isabelle Le Ber
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
| | - Alexis Brice
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
| | - Morwena Latouche
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- EPHE, Neurogenetics Team, PSL Research University, Paris, France
- *Correspondence: Morwena Latouche,
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13
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Maharjan N, Saxena S. Models of Neurodegenerative Diseases. Neurogenetics 2023. [DOI: 10.1007/978-3-031-07793-7_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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14
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Kartanou C, Kontogeorgiou Z, Rentzos M, Potagas C, Aristeidou S, Kapaki E, Paraskevas GP, Constantinides VC, Stefanis L, Papageorgiou SG, Houlden H, Panas M, Koutsis G, Karadima G. Expanding the spectrum of C9ORF72-related neurodegenerative disorders in the Greek population. J Neurol Sci 2022; 442:120450. [PMID: 36252286 DOI: 10.1016/j.jns.2022.120450] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 09/26/2022] [Accepted: 10/01/2022] [Indexed: 10/31/2022]
Abstract
The C9ORF72 hexanucleotide repeat expansion is an established cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and has also been associated with Huntington disease (HD)-like syndromes and rarely with Parkinson's disease (PD) and Alzheimer's disease (AD). In the present study we aimed to investigate the genotypic and phenotypic profile of C9ORF72-related disorders in Greece. For this reason, 957 patients (467 with ALS, 53 with HD-like syndromes, 247 with dementia, 175 with PD and 15 with hereditary spastic paraplegia, HSP) and 321 controls were tested for the C9ORF72 repeat expansion. Forty-nine patients with ALS (10.5%), 2 with HD-like syndromes (3.8%), 13 with FTD (11.5%), 1 with AD (1.6%), and 2 with PD (1.1%) were expansion-positive. The expansion was not detected in the HSP or control groups. The results of this study provide an update on the spectrum of C9ORF72-related neurodegenerative diseases, emphasizing the importance of C9ORF72 genetic testing in Greek patients with familial and sporadic ALS and/or FTD and HD-like syndromes.
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Affiliation(s)
- Chrisoula Kartanou
- Neurogenetics Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.
| | - Zoi Kontogeorgiou
- Neurogenetics Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Michail Rentzos
- 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Constantin Potagas
- Neuropsychology and Speech Pathology Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Stavroula Aristeidou
- Neurogenetics Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Elisabeth Kapaki
- Unit of Neurochemistry and Biological Markers, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - George P Paraskevas
- Unit of Neurochemistry and Biological Markers, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Vasilios C Constantinides
- Unit of Neurochemistry and Biological Markers, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Leonidas Stefanis
- 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece; Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Greece
| | - Sokratis G Papageorgiou
- 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Henry Houlden
- MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK
| | - Marios Panas
- Neurogenetics Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgios Koutsis
- Neurogenetics Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgia Karadima
- Neurogenetics Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
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15
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Urso D, Zoccolella S, Gnoni V, Logroscino G. Amyotrophic Lateral Sclerosis-The Complex Phenotype-From an Epidemiological Perspective: A Focus on Extrapyramidal and Non-Motor Features. Biomedicines 2022; 10:biomedicines10102537. [PMID: 36289799 PMCID: PMC9599737 DOI: 10.3390/biomedicines10102537] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 09/24/2022] [Accepted: 09/28/2022] [Indexed: 11/16/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease (MND) and has emerged, among the disorders, with the largest increase in incidence in Western countries. Although the typical clinical phenotype of ALS involves simultaneous upper and lower motor neurons, there is growing evidence that the neurodegeneration during the course of the disease can also involve other motor and non-motor regions. In this review, we analyzed and discussed available data from epidemiological population-based studies on extrapyramidal and non-motor features during the course of ALS.
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Affiliation(s)
- Daniele Urso
- Center for Neurodegenerative Diseases and the Aging Brain, Department of Clinical Research in Neurology, University of Bari ‘Aldo Moro’, “Pia Fondazione Cardinale G. Panico”, 73039 Tricase, Italy
- Department of Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, De Crespigny Park, London SE5 8AF, UK
- Correspondence: (D.U.); (G.L.)
| | - Stefano Zoccolella
- Center for Neurodegenerative Diseases and the Aging Brain, Department of Clinical Research in Neurology, University of Bari ‘Aldo Moro’, “Pia Fondazione Cardinale G. Panico”, 73039 Tricase, Italy
| | - Valentina Gnoni
- Center for Neurodegenerative Diseases and the Aging Brain, Department of Clinical Research in Neurology, University of Bari ‘Aldo Moro’, “Pia Fondazione Cardinale G. Panico”, 73039 Tricase, Italy
- Department of Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, De Crespigny Park, London SE5 8AF, UK
| | - Giancarlo Logroscino
- Center for Neurodegenerative Diseases and the Aging Brain, Department of Clinical Research in Neurology, University of Bari ‘Aldo Moro’, “Pia Fondazione Cardinale G. Panico”, 73039 Tricase, Italy
- Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari ‘Aldo Moro’, 70121 Bari, Italy
- Correspondence: (D.U.); (G.L.)
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16
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Logroscino G, Urso D, Tortelli R. The challenge of amyotrophic lateral sclerosis descriptive epidemiology: to estimate low incidence rates across complex phenotypes in different geographic areas. Curr Opin Neurol 2022; 35:678-685. [PMID: 35946801 PMCID: PMC9593328 DOI: 10.1097/wco.0000000000001097] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
PURPOSE OF REVIEW Amyotrophic lateral sclerosis (ALS) is a rare progressive neurodegenerative disease of motor neurons with a fatal outcome. The rareness of the disease and the rapidly fatal course are the main challenges for the ALS epidemiological research. The understanding of ALS has clearly advanced in the recent years both in the genetics and in the leading pathways of disease determinants. Epidemiological research has played a primary role in these discoveries. RECENT FINDINGS Epidemiological studies have shown a variation of incidence, mortality and prevalence of ALS between geographical areas and different populations, supporting the notion that genetic factors, linked to populations' ancestries, along with environmental and lifestyle factors, play a significant role in the occurrence of the disease. The burden of motor neuron diseases is increasing and currently more relevant in high-income countries but increasing at the highest rate in low and middle-income countries. The ALS phenotype is not restricted to motor functions. C9orf72 repeat expansion seems to present a recognizable phenotype characterized by earlier disease onset, the presence of cognitive and behavioural impairment. SUMMARY Population-based disease registries have played a major role in developing new knowledge on ALS, in characterizing genotype-phenotype correlations, in discovering new genetic modifiers and finally in planning research and health services, considering the high cost of motor neuron disease care. Epidemiological research based on multicentre international collaboration is essential to provide new data on ALS, especially in some regions of the world with poor data.
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Affiliation(s)
- Giancarlo Logroscino
- Center for Neurodegenerative Diseases and the Aging Brain, Department of Clinical Research in Neurology, University of Bari ’Aldo Moro’, “Pia Fondazione Cardinale G. Panico”, Tricase, Lecce
- Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari ’Aldo Moro’, Bari, Italy
| | - Daniele Urso
- Center for Neurodegenerative Diseases and the Aging Brain, Department of Clinical Research in Neurology, University of Bari ’Aldo Moro’, “Pia Fondazione Cardinale G. Panico”, Tricase, Lecce
- Department of Neurosciences, King's College London, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, London, UK
| | - Rosanna Tortelli
- Neuroscience and Rare Diseases Discovery and Translational Area, Roche Pharma Research and Early Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland
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17
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Carlos AF, Josephs KA. Frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43): its journey of more than 100 years. J Neurol 2022; 269:4030-4054. [PMID: 35320398 PMCID: PMC10184567 DOI: 10.1007/s00415-022-11073-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 03/05/2022] [Accepted: 03/08/2022] [Indexed: 10/18/2022]
Abstract
Frontotemporal lobar degeneration (FTLD) with TDP-43-immunoreactive inclusions (FTLD-TDP) is a neurodegenerative disease associated with clinical, genetic, and neuropathological heterogeneity. An association between TDP-43, FTLD and amyotrophic lateral sclerosis (ALS) was first described in 2006. However, a century before immunohistochemistry existed, atypical dementias displaying behavioral, language and/or pyramidal symptoms and showing non-specific FTLD with superficial cortical neuronal loss, gliosis and spongiosis were often confused with Alzheimer's or Pick's disease. Initially this pathology was termed dementia lacking distinctive histopathology (DLDH), but this was later renamed when ubiquitinated inclusions originally found in ALS were also discovered in (DLDH), thus warranting a recategorization as FTLD-U (ubiquitin). Finally, the ubiquitinated protein was identified as TDP-43, which aggregates in cortical, subcortical, limbic and brainstem neurons and glial cells. The topography and morphology of TDP-43 inclusions associate with specific clinical syndromes and genetic mutations which implies different pathomechanisms that are yet to be discovered; hence, the TDP-43 journey has actually just begun. In this review, we describe how FTLD-TDP was established and defined clinically and neuropathologically throughout the past century.
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Affiliation(s)
- Arenn F Carlos
- Department of Neurology, Mayo Clinic, 200 1st St S.W, Rochester, MN, 55905, USA
| | - Keith A Josephs
- Department of Neurology, Mayo Clinic, 200 1st St S.W, Rochester, MN, 55905, USA.
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18
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Zampatti S, Peconi C, Campopiano R, Gambardella S, Caltagirone C, Giardina E. C9orf72-Related Neurodegenerative Diseases: From Clinical Diagnosis to Therapeutic Strategies. Front Aging Neurosci 2022; 14:907122. [PMID: 35754952 PMCID: PMC9226392 DOI: 10.3389/fnagi.2022.907122] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/16/2022] [Indexed: 11/13/2022] Open
Abstract
Hexanucleotide expansion in C9orf72 has been related to several phenotypes to date, complicating the clinical recognition of these neurodegenerative disorders. An early diagnosis can improve the management of patients, promoting early administration of therapeutic supportive strategies. Here, we report known clinical presentations of C9orf72-related neurodegenerative disorders, pointing out suggestive phenotypes that can benefit the genetic characterization of patients. Considering the high variability of C9orf72-related disorder, frequent and rare manifestations are described, with detailed clinical, instrumental evaluation, and supportive therapeutical approaches. Furthermore, to improve the understanding of molecular pathways of the disease and potential therapeutical targets, a detailed description of the cellular mechanisms related to the pathological effect of C9orf72 is reported. New promising therapeutical strategies and ongoing studies are reported highlighting their molecular role in cellular pathological pathways of C9orf72. These therapeutic approaches are particularly promising because they seem to stop the disease before neuronal damage. The knowledge of clinical and molecular features of C9orf72-related neurodegenerative disorders improves the therapeutical application of known strategies and will lay the basis for the development of new potential therapies.
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Affiliation(s)
- Stefania Zampatti
- Genomic Medicine Laboratory UILDM, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Cristina Peconi
- Genomic Medicine Laboratory UILDM, IRCCS Fondazione Santa Lucia, Rome, Italy
| | | | - Stefano Gambardella
- IRCCS Neuromed, Pozzilli, Italy.,Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy
| | - Carlo Caltagirone
- Department of Clinical and Behavioral Neurology, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Emiliano Giardina
- Genomic Medicine Laboratory UILDM, IRCCS Fondazione Santa Lucia, Rome, Italy.,Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy
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19
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Breevoort S, Gibson S, Figueroa K, Bromberg M, Pulst S. Expanding Clinical Spectrum of C9ORF72-Related Disorders and Promising Therapeutic Strategies: A Review. Neurol Genet 2022; 8:e670. [PMID: 35620137 PMCID: PMC9128039 DOI: 10.1212/nxg.0000000000000670] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 03/18/2022] [Indexed: 11/15/2022]
Abstract
In 2011, a pathogenic hexanucleotide repeat expansion in the C9ORF72 gene was discovered to be the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Before this, the C9ORF72 gene and its protein were unknown. The repeat expansion was found to cause both haploinsufficiency and gain of toxicity through aggregating RNA products and dipeptide repeat proteins. A worldwide effort was then initiated to define C9ORF72 ALS/FTD and unravel the pathogenic mechanism for the development of therapeutic options. A decade later, C9ORF72 genetic testing is readily available. There is now an increasing appreciation that C9ORF72 not only is the leading genetic cause of ALS/FTD but may contribute to a spectrum of disorders. This article reviews what is currently known about the C9ORF72 expansion and how C9ORF72 expansion manifests in ALS, FTD, psychiatric disorders, and movement disorders. With therapeutic strategies fast approaching the clinic, earlier recognition of possible C9ORF72 expansion related disorders is even more paramount to improve patient care.
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Affiliation(s)
| | - Summer Gibson
- Department of Neurology, University of Utah, Salt Lake City
| | - Karla Figueroa
- Department of Neurology, University of Utah, Salt Lake City
| | - Mark Bromberg
- Department of Neurology, University of Utah, Salt Lake City
| | - Stefan Pulst
- Department of Neurology, University of Utah, Salt Lake City
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20
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Koçoğlu C, Van Broeckhoven C, van der Zee J. How network-based approaches can complement gene identification studies in frontotemporal dementia. Trends Genet 2022; 38:944-955. [DOI: 10.1016/j.tig.2022.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 05/04/2022] [Accepted: 05/04/2022] [Indexed: 11/17/2022]
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21
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Dhasmana S, Dhasmana A, Narula AS, Jaggi M, Yallapu MM, Chauhan SC. The panoramic view of amyotrophic lateral sclerosis: A fatal intricate neurological disorder. Life Sci 2022; 288:120156. [PMID: 34801512 DOI: 10.1016/j.lfs.2021.120156] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 11/10/2021] [Accepted: 11/11/2021] [Indexed: 02/07/2023]
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disease affecting both upper and lower motor neurons. In the United States alone, there are 16,000-20,000 established cases of ALS. The early disease diagnosis is challenging due to many overlapping pathophysiologies with other neurological diseases. The etiology of ALS is unknown; however, it is divided into two categories: familial ALS (fALS) which occurs due to gene mutations & contributes to 5-10% of ALS, and sporadic ALS (sALS) which is due to environmental factors & contributes to 90-95% of ALS. There is still no curative treatment for ALS: palliative care and symptomatic treatment are therefore essential components in the management of these patients. In this review, we provide a panoramic view of ALS, which includes epidemiology, risk factors, pathophysiologies, biomarkers, diagnosis, therapeutics (natural, synthetic, gene-based, pharmacological, stem cell, extracellular vesicles, and physical therapy), controversies (in the clinical trials of ALS), the scope of nanomedicine in ALS, and future perspectives.
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Affiliation(s)
- Swati Dhasmana
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA; South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Anupam Dhasmana
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA; South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Acharan S Narula
- Narula Research LLC, 107 Boulder Bluff, Chapel Hill, NC 27516, USA
| | - Meena Jaggi
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA; South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Murali M Yallapu
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA; South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Subhash C Chauhan
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA; South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA.
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22
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Jiang L, Zhang T, Lu K, Qi S. The progress in C9orf72 research: ALS/FTD pathogenesis, functions and structure. Small GTPases 2022; 13:56-76. [PMID: 33663328 PMCID: PMC9707547 DOI: 10.1080/21541248.2021.1892443] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The hexanucleotide repeat (GGGGCC) expansion in C9orf72 is accounted for a large proportion of the genetic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The hypotheses of how the massive G4C2 repeats in C9orf72 destroy the neurons and lead to ALS/FTD are raised and improving. As a multirole player, C9orf72 exerts critical roles in many cellular processes, including autophagy, membrane trafficking, immune response, and so on. Notably, the partners of C9orf72, through which C9orf72 participates in the cell activities, have been identified. Notably, the structures of the C9orf72-SMCR8-WDR41 complex shed light on its activity as GTPase activating proteins (GAP). In this manuscript, we reviewed the latest research progress in the C9orf72-mediated ALS/FTD, the physiological functions of C9orf72, and the putative function models of C9orf72/C9orf72-containing complex.
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Affiliation(s)
- Lan Jiang
- Department of Urology, State Key Laboratory of Biotherapy, West China Hospital, College of Life Sciences, Sichuan University, Chengdu, China
| | - Tizhong Zhang
- Department of Urology, State Key Laboratory of Biotherapy, West China Hospital, College of Life Sciences, Sichuan University, Chengdu, China
| | - Kefeng Lu
- Department of Urology, State Key Laboratory of Biotherapy, West China Hospital, College of Life Sciences, Sichuan University, Chengdu, China
| | - Shiqian Qi
- Department of Urology, State Key Laboratory of Biotherapy, West China Hospital, College of Life Sciences, Sichuan University, Chengdu, China,CONTACT Shiqian Qi Department of Urology, State Key Laboratory of Biotherapy, West China Hospital, College of Life Sciences, Sichuan University, Chengdu, China.
These authors contributed equally to this work.
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23
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Wang H, Kodavati M, Britz GW, Hegde ML. DNA Damage and Repair Deficiency in ALS/FTD-Associated Neurodegeneration: From Molecular Mechanisms to Therapeutic Implication. Front Mol Neurosci 2021; 14:784361. [PMID: 34975400 PMCID: PMC8716463 DOI: 10.3389/fnmol.2021.784361] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/25/2021] [Indexed: 02/03/2023] Open
Abstract
Emerging studies reveal that neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are commonly linked to DNA damage accumulation and repair deficiency. Neurons are particularly vulnerable to DNA damage due to their high metabolic activity, relying primarily on oxidative phosphorylation, which leads to increased reactive oxygen species (ROS) generation and subsequent DNA damage. Efficient and timely repair of such damage is critical for guarding the integrity of genomic DNA and for cell survival. Several genes predominantly associated with RNA/DNA metabolism have been implicated in both ALS and FTD, suggesting that the two diseases share a common underlying pathology with varied clinical manifestations. Recent studies reveal that many of the gene products, including RNA/DNA binding proteins (RBPs) TDP-43 and FUS are involved in diverse DNA repair pathways. A key question in the etiology of the ALS/FTD spectrum of neurodegeneration is the mechanisms and pathways involved in genome instability caused by dysfunctions/mutations of those RBP genes and their consequences in the central nervous system. The understanding of such converging molecular mechanisms provides insights into the underlying etiology of the rapidly progressing neurodegeneration in ALS/FTD, while also revealing novel DNA repair target avenues for therapeutic development. In this review, we summarize the common mechanisms of neurodegeneration in ALS and FTD, with a particular emphasis on the DNA repair defects induced by ALS/FTD causative genes. We also highlight the consequences of DNA repair defects in ALS/FTD and the therapeutic potential of DNA damage repair-targeted amelioration of neurodegeneration.
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Affiliation(s)
- Haibo Wang
- Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, United States
- Department of Neuroscience Research at Neurological Surgery, Weill Medical College, New York, NY, United States
| | - Manohar Kodavati
- Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, United States
| | - Gavin W. Britz
- Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, United States
- Department of Neuroscience Research at Neurological Surgery, Weill Medical College, New York, NY, United States
| | - Muralidhar L. Hegde
- Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, United States
- Department of Neuroscience Research at Neurological Surgery, Weill Medical College, New York, NY, United States
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24
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Root J, Merino P, Nuckols A, Johnson M, Kukar T. Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis. Neurobiol Dis 2021; 154:105360. [PMID: 33812000 PMCID: PMC8113138 DOI: 10.1016/j.nbd.2021.105360] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 03/16/2021] [Accepted: 03/29/2021] [Indexed: 12/11/2022] Open
Abstract
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative disorders that are thought to exist on a clinical and pathological spectrum. FTD and ALS are linked by shared genetic causes (e.g. C9orf72 hexanucleotide repeat expansions) and neuropathology, such as inclusions of ubiquitinated, misfolded proteins (e.g. TAR DNA-binding protein 43; TDP-43) in the CNS. Furthermore, some genes that cause FTD or ALS when mutated encode proteins that localize to the lysosome or modulate endosome-lysosome function, including lysosomal fusion, cargo trafficking, lysosomal acidification, autophagy, or TFEB activity. In this review, we summarize evidence that lysosomal dysfunction, caused by genetic mutations (e.g. C9orf72, GRN, MAPT, TMEM106B) or toxic-gain of function (e.g. aggregation of TDP-43 or tau), is an important pathogenic disease mechanism in FTD and ALS. Further studies into the normal function of many of these proteins are required and will help uncover the mechanisms that cause lysosomal dysfunction in FTD and ALS. Mutations or polymorphisms in genes that encode proteins important for endosome-lysosome function also occur in other age-dependent neurodegenerative diseases, including Alzheimer's (e.g. APOE, PSEN1, APP) and Parkinson's (e.g. GBA, LRRK2, ATP13A2) disease. A more complete understanding of the common and unique features of lysosome dysfunction across the spectrum of neurodegeneration will help guide the development of therapies for these devastating diseases.
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Affiliation(s)
- Jessica Root
- Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta 30322, Georgia; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta 30322, Georgia
| | - Paola Merino
- Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta 30322, Georgia; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta 30322, Georgia
| | - Austin Nuckols
- Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta 30322, Georgia; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta 30322, Georgia
| | - Michelle Johnson
- Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta 30322, Georgia; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta 30322, Georgia
| | - Thomas Kukar
- Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta 30322, Georgia; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta 30322, Georgia; Department of Neurology, Emory University, School of Medicine, Atlanta 30322, Georgia.
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25
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Disease Mechanisms and Therapeutic Approaches in C9orf72 ALS-FTD. Biomedicines 2021; 9:biomedicines9060601. [PMID: 34070550 PMCID: PMC8229688 DOI: 10.3390/biomedicines9060601] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/19/2021] [Accepted: 05/20/2021] [Indexed: 01/15/2023] Open
Abstract
A hexanucleotide repeat expansion mutation in the first intron of C9orf72 is the most common known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Since the discovery in 2011, numerous pathogenic mechanisms, including both loss and gain of function, have been proposed. The body of work overall suggests that toxic gain of function arising from bidirectionally transcribed repeat RNA is likely to be the primary driver of disease. In this review, we outline the key pathogenic mechanisms that have been proposed to date and discuss some of the novel therapeutic approaches currently in development.
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26
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Smeyers J, Banchi EG, Latouche M. C9ORF72: What It Is, What It Does, and Why It Matters. Front Cell Neurosci 2021; 15:661447. [PMID: 34025358 PMCID: PMC8131521 DOI: 10.3389/fncel.2021.661447] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 03/17/2021] [Indexed: 12/11/2022] Open
Abstract
When the non-coding repeat expansion in the C9ORF72 gene was discovered to be the most frequent cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in 2011, this gene and its derived protein, C9ORF72, were completely unknown. The mutation appeared to produce both haploinsufficiency and gain-of-function effects in the form of aggregating expanded RNAs and dipeptide repeat proteins (DPRs). An unprecedented effort was then unleashed to decipher the pathogenic mechanisms and the functions of C9ORF72 in order to design therapies. A decade later, while the toxicity of accumulating gain-of-function products has been established and therapeutic strategies are being developed to target it, the contribution of the loss of function starts to appear more clearly. This article reviews the current knowledge about the C9ORF72 protein, how it is affected by the repeat expansion in models and patients, and what could be the contribution of its haploinsufficiency to the disease in light of the most recent findings. We suggest that these elements should be taken into consideration to refine future therapeutic strategies, compensating for the decrease of C9ORF72 or at least preventing a further reduction.
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Affiliation(s)
- Julie Smeyers
- Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, DMU Neuroscience 6, Paris, France
- PSL Research university, EPHE, Neurogenetics team, Paris, France
| | - Elena-Gaia Banchi
- Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, DMU Neuroscience 6, Paris, France
| | - Morwena Latouche
- Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, DMU Neuroscience 6, Paris, France
- PSL Research university, EPHE, Neurogenetics team, Paris, France
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27
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Zhao G, Liu Z, Wang M, Yuan Y, Ni J, Li W, Huang L, Hu Y, Liu P, Hou X, Guo J, Jiang H, Shen L, Tang B, Li J, Wang J. Gene4MND: An Integrative Genetic Database and Analytic Platform for Motor Neuron Disease. Front Mol Neurosci 2021; 14:644202. [PMID: 33867934 PMCID: PMC8047132 DOI: 10.3389/fnmol.2021.644202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 03/04/2021] [Indexed: 12/12/2022] Open
Affiliation(s)
- Guihu Zhao
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.,Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, China
| | - Zhen Liu
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Mengli Wang
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yanchun Yuan
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Jie Ni
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Wanzhen Li
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Ling Huang
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yiting Hu
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Pan Liu
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaorong Hou
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Jifeng Guo
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Medical Genetics, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China.,Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
| | - Hong Jiang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Medical Genetics, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China.,Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
| | - Lu Shen
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Medical Genetics, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China.,Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
| | - Beisha Tang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Medical Genetics, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China.,Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
| | - Jinchen Li
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.,Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Medical Genetics, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China
| | - Junling Wang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Medical Genetics, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China.,Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
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28
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Schmitz A, Pinheiro Marques J, Oertig I, Maharjan N, Saxena S. Emerging Perspectives on Dipeptide Repeat Proteins in C9ORF72 ALS/FTD. Front Cell Neurosci 2021; 15:637548. [PMID: 33679328 PMCID: PMC7930069 DOI: 10.3389/fncel.2021.637548] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 01/07/2021] [Indexed: 11/13/2022] Open
Abstract
The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide expansion in the chromosome 9 open reading frame 72 gene (C9ORF72). This hexanucleotide expansion consists of GGGGCC (G4C2) repeats that have been implicated to lead to three main modes of disease pathology: loss of function of the C9ORF72 protein, the generation of RNA foci, and the production of dipeptide repeat proteins (DPRs) through repeat-associated non-AUG (RAN) translation. Five different DPRs are currently known to be formed: glycine-alanine (GA) and glycine-arginine (GR) from the sense strand, proline-alanine (PA), and proline-arginine (PR) from the antisense strand, and glycine-proline (GP) from both strands. The exact contribution of each DPR to disease pathology is currently under intense scrutiny and is still poorly understood. However, recent advances in both neuropathological and cellular studies have provided us with clues enabling us to better understand the effect of individual DPRs on disease pathogenesis. In this review, we compile the current knowledge of specific DPR involvement on disease development and highlight recent advances, such as the impact of arginine-rich DPRs on nucleolar protein quality control, the correlation of poly-GR with neurodegeneration, and the possible involvement of chimeric DPR species. Further, we discuss recent findings regarding the mechanisms of RAN translation, its modulators, and other promising therapeutic options.
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Affiliation(s)
- Alexander Schmitz
- Department of Neurology, Center for Experimental Neurology, Inselspital University Hospital, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - João Pinheiro Marques
- Department of Neurology, Center for Experimental Neurology, Inselspital University Hospital, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Irina Oertig
- Department of Neurology, Center for Experimental Neurology, Inselspital University Hospital, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Niran Maharjan
- Department of Neurology, Center for Experimental Neurology, Inselspital University Hospital, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Smita Saxena
- Department of Neurology, Center for Experimental Neurology, Inselspital University Hospital, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
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29
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Roggenbuck J. C9orf72 and the Care of the Patient With ALS or FTD: Progress and Recommendations After 10 Years. NEUROLOGY-GENETICS 2020; 7:e542. [PMID: 33575483 PMCID: PMC7862089 DOI: 10.1212/nxg.0000000000000542] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 10/19/2020] [Indexed: 12/12/2022]
Abstract
The 2011 discovery of the pathogenic hexanucleotide repeat expansion (HRE) in C9orf72, the leading genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), marked a breakthrough in the effort to unravel the etiology of these conditions. Ten years later, clinicians are still working to integrate the implications of this discovery into the care of individuals with ALS and/or FTD. Consensus management guidelines for ALS do not comprehensively address the issue of genetic testing, and questions remain about whom to test, what counseling should be provided before and after testing, laboratory methods, and test interpretation. These challenges have contributed to inconsistent clinical practices and present barriers to patients wishing to access testing. This review summarizes the clinical impact of the discovery of the C9orf72 HRE, outlines ongoing challenges, and provides recommendations for C9orf72 testing, counseling, and research.
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Affiliation(s)
- Jennifer Roggenbuck
- Departments of Neurology and Internal Medicine, The Ohio State University Wexner Medical Center, Columbus
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30
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Castellanos-Montiel MJ, Chaineau M, Durcan TM. The Neglected Genes of ALS: Cytoskeletal Dynamics Impact Synaptic Degeneration in ALS. Front Cell Neurosci 2020; 14:594975. [PMID: 33281562 PMCID: PMC7691654 DOI: 10.3389/fncel.2020.594975] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 10/21/2020] [Indexed: 12/11/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that selectively affects motor neurons (MNs) of the cortex, brainstem, and spinal cord. Several genes have been linked to both familial (fALS) and sporadic (sALS) cases of ALS. Among all the ALS-related genes, a group of genes known to directly affect cytoskeletal dynamics (ALS2, DCTN1, PFN1, KIF5A, NF-L, NF-H, PRPH, SPAST, and TUBA4A) is of high importance for MN health and survival, considering that MNs are large polarized cells with axons that can reach up to 1 m in length. In particular, cytoskeletal dynamics facilitate the transport of organelles and molecules across the long axonal distances within the cell, playing a key role in synapse maintenance. The majority of ALS-related genes affecting cytoskeletal dynamics were identified within the past two decades, making it a new area to explore for ALS. The purpose of this review is to provide insights into ALS-associated cytoskeletal genes and outline how recent studies have pointed towards novel pathways that might be impacted in ALS. Further studies making use of extensive analysis models to look for true hits, the newest technologies such as CRIPSR/Cas9, human induced pluripotent stem cells (iPSCs) and axon sequencing, as well as the development of more transgenic animal models could potentially help to: differentiate the variants that truly act as a primary cause of the disease from the ones that act as risk factors or disease modifiers, identify potential interactions between two or more ALS-related genes in disease onset and progression and increase our understanding of the molecular mechanisms leading to cytoskeletal defects. Altogether, this information will give us a hint on the real contribution of the cytoskeletal ALS-related genes during this lethal disease.
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Affiliation(s)
| | - Mathilde Chaineau
- Early Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada
| | - Thomas M Durcan
- Early Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada
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Shatunov A, Al-Chalabi A. The genetic architecture of ALS. Neurobiol Dis 2020; 147:105156. [PMID: 33130222 DOI: 10.1016/j.nbd.2020.105156] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 10/27/2020] [Accepted: 10/27/2020] [Indexed: 12/12/2022] Open
Affiliation(s)
- Aleksey Shatunov
- Department of Basic & Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 9RX, UK
| | - Ammar Al-Chalabi
- Department of Basic & Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 9RX, UK; Department of Neurology, King's College Hospital, London SE5 9RS, UK.
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Iacoangeli A, Lin T, Al Khleifat A, Jones AR, Opie-Martin S, Coleman JRI, Shatunov A, Sproviero W, Williams KL, Garton F, Restuadi R, Henders AK, Mather KA, Needham M, Mathers S, Nicholson GA, Rowe DB, Henderson R, McCombe PA, Pamphlett R, Blair IP, Schultz D, Sachdev PS, Newhouse SJ, Proitsi P, Fogh I, Ngo ST, Dobson RJB, Wray NR, Steyn FJ, Al-Chalabi A. Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics. Cell Rep 2020; 33:108323. [PMID: 33113361 PMCID: PMC7610013 DOI: 10.1016/j.celrep.2020.108323] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 07/28/2020] [Accepted: 10/07/2020] [Indexed: 12/12/2022] Open
Abstract
We meta-analyze amyotrophic lateral sclerosis (ALS) genome-wide association study (GWAS) data of European and Chinese populations (84,694 individuals). We find an additional significant association between rs58854276 spanning ACSL5-ZDHHC6 with ALS (p = 8.3 × 10-9), with replication in an independent Australian cohort (1,502 individuals; p = 0.037). Moreover, B4GALNT1, G2E3-SCFD1, and TRIP11-ATXN3 are identified using a gene-based analysis. ACSL5 has been associated with rapid weight loss, as has another ALS-associated gene, GPX3. Weight loss is frequent in ALS patients and is associated with shorter survival. We investigate the effect of the ACSL5 and GPX3 single-nucleotide polymorphisms (SNPs), using longitudinal body composition and weight data of 77 patients and 77 controls. In patients' fat-free mass, although not significant, we observe an effect in the expected direction (rs58854276: -2.1 ± 1.3 kg/A allele, p = 0.053; rs3828599: -1.0 ± 1.3 kg/A allele, p = 0.22). No effect was observed in controls. Our findings support the increasing interest in lipid metabolism in ALS and link the disease genetics to weight loss in patients.
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Affiliation(s)
- Alfredo Iacoangeli
- Department of Biostatistics and Health Informatics, King's College London, London, UK; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK; National Institute for Health Research Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and King's College London, London, UK.
| | - Tian Lin
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Brisbane QLD 4072, Australia
| | - Ahmad Al Khleifat
- Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK
| | - Ashley R Jones
- Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK
| | - Sarah Opie-Martin
- Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK
| | - Jonathan R I Coleman
- National Institute for Health Research Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and King's College London, London, UK; Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Aleksey Shatunov
- Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK
| | - William Sproviero
- Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK
| | - Kelly L Williams
- Centre for Motor Neuron Disease Research, Macquarie University, Sidney NSW 2109, Australia
| | - Fleur Garton
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Brisbane QLD 4072, Australia
| | - Restuadi Restuadi
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Brisbane QLD 4072, Australia
| | - Anjali K Henders
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Brisbane QLD 4072, Australia
| | - Karen A Mather
- Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney NSW, Australia; Neuroscience Research Australia, Randwick NSW, Australia
| | - Merilee Needham
- Fiona Stanley Hospital, 11 Robin Warren Drive, Murdoch Perth WA 6150, Australia; Notre Dame University, 32 Mouat Street, Fremantle WA 6160, Australia; Murdoch University, 90 South Street, Murdoch WA 6150, Australia
| | - Susan Mathers
- Calvary Health Care Bethlehem, Parkdale VIC 3195, Australia
| | - Garth A Nicholson
- ANZAC Research Institute, Concord Repatriation General Hospital, Sydney NSW 2139, Australia
| | - Dominic B Rowe
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Robert Henderson
- Centre for Clinical Research, The University of Queensland, Brisbane QLD, Australia; Queensland Brain Institute, The University of Queensland, Brisbane QLD, Australia
| | - Pamela A McCombe
- Centre for Clinical Research, The University of Queensland, Brisbane QLD, Australia; Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane QLD, Australia
| | - Roger Pamphlett
- Brain and Mind Centre, The University of Sydney, Sydney NSW, Australia
| | - Ian P Blair
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - David Schultz
- Flinders Medical Centre, Bedford Park SA 5042, Australia
| | - Perminder S Sachdev
- Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney NSW, Australia; Neuropsychiatric Institute, Prince of Wales Hospital, Sydney NSW Australia
| | - Stephen J Newhouse
- Department of Biostatistics and Health Informatics, King's College London, London, UK; National Institute for Health Research Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and King's College London, London, UK; Institute of Health Informatics, University College London, London, UK
| | - Petroula Proitsi
- Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK
| | - Isabella Fogh
- Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK; Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Shyuan T Ngo
- Centre for Clinical Research, The University of Queensland, Brisbane QLD, Australia; Queensland Brain Institute, The University of Queensland, Brisbane QLD, Australia; Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane QLD, Australia; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane QLD, Australia
| | - Richard J B Dobson
- Department of Biostatistics and Health Informatics, King's College London, London, UK; National Institute for Health Research Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and King's College London, London, UK; Institute of Health Informatics, University College London, London, UK
| | - Naomi R Wray
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Brisbane QLD 4072, Australia; Queensland Brain Institute, The University of Queensland, Brisbane QLD, Australia
| | - Frederik J Steyn
- Centre for Clinical Research, The University of Queensland, Brisbane QLD, Australia; Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane QLD, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane QLD, Australia
| | - Ammar Al-Chalabi
- Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK; King's College Hospital, Bessemer Road, London SE5 9RS, UK
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Lattante S, Marangi G, Doronzio PN, Conte A, Bisogni G, Zollino M, Sabatelli M. High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines. Genes (Basel) 2020; 11:genes11101123. [PMID: 32987860 PMCID: PMC7600768 DOI: 10.3390/genes11101123] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/15/2020] [Accepted: 09/22/2020] [Indexed: 12/17/2022] Open
Abstract
The development of high-throughput sequencing technologies and screening of big patient cohorts with familial and sporadic amyotrophic lateral sclerosis (ALS) led to the identification of a significant number of genetic variants, which are sometimes difficult to interpret. The American College of Medical Genetics and Genomics (ACMG) provided guidelines to help molecular geneticists and pathologists to interpret variants found in laboratory testing. We assessed the application of the ACMG criteria to ALS-related variants, combining data from literature with our experience. We analyzed a cohort of 498 ALS patients using massive parallel sequencing of ALS-associated genes and identified 280 variants with a minor allele frequency < 1%. Examining all variants using the ACMG criteria, thus considering the type of variant, inheritance, familial segregation, and possible functional studies, we classified 20 variants as “pathogenic”. In conclusion, ALS’s genetic complexity, such as oligogenic inheritance, presence of genes acting as risk factors, and reduced penetrance, needs to be considered when interpreting variants. The goal of this work is to provide helpful suggestions to geneticists and clinicians dealing with ALS.
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Affiliation(s)
- Serena Lattante
- Section of Genomic Medicine, Department of Life Sciences and Public Health, Faculty of Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Roma, Italy; (S.L.); (P.N.D.); (M.Z.)
- Complex Operational Unit of Medical Genetics, Department of Laboratory and Infectious Disease Sciences, A. Gemelli University Hospital Foundation IRCCS, 00168 Roma, Italy
| | - Giuseppe Marangi
- Section of Genomic Medicine, Department of Life Sciences and Public Health, Faculty of Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Roma, Italy; (S.L.); (P.N.D.); (M.Z.)
- Complex Operational Unit of Medical Genetics, Department of Laboratory and Infectious Disease Sciences, A. Gemelli University Hospital Foundation IRCCS, 00168 Roma, Italy
- Correspondence: ; Tel.: +39-0630154606
| | - Paolo Niccolò Doronzio
- Section of Genomic Medicine, Department of Life Sciences and Public Health, Faculty of Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Roma, Italy; (S.L.); (P.N.D.); (M.Z.)
- Complex Operational Unit of Medical Genetics, Department of Laboratory and Infectious Disease Sciences, A. Gemelli University Hospital Foundation IRCCS, 00168 Roma, Italy
| | - Amelia Conte
- Adult NEMO Clinical Center, Complex Operational Unit of Neurology, Department of Aging, Neurological, Orthopedic and Head-Neck Sciences, A. Gemelli University Hospital Foundation IRCCS, 00168 Roma, Italy; (A.C.); (G.B.); (M.S.)
| | - Giulia Bisogni
- Adult NEMO Clinical Center, Complex Operational Unit of Neurology, Department of Aging, Neurological, Orthopedic and Head-Neck Sciences, A. Gemelli University Hospital Foundation IRCCS, 00168 Roma, Italy; (A.C.); (G.B.); (M.S.)
| | - Marcella Zollino
- Section of Genomic Medicine, Department of Life Sciences and Public Health, Faculty of Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Roma, Italy; (S.L.); (P.N.D.); (M.Z.)
- Complex Operational Unit of Medical Genetics, Department of Laboratory and Infectious Disease Sciences, A. Gemelli University Hospital Foundation IRCCS, 00168 Roma, Italy
| | - Mario Sabatelli
- Adult NEMO Clinical Center, Complex Operational Unit of Neurology, Department of Aging, Neurological, Orthopedic and Head-Neck Sciences, A. Gemelli University Hospital Foundation IRCCS, 00168 Roma, Italy; (A.C.); (G.B.); (M.S.)
- Section of Neurology, Department of Neuroscience, Faculty of Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Roma, Italy
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Kim T, Song B, Lee IS. Drosophila Glia: Models for Human Neurodevelopmental and Neurodegenerative Disorders. Int J Mol Sci 2020; 21:E4859. [PMID: 32660023 PMCID: PMC7402321 DOI: 10.3390/ijms21144859] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/27/2020] [Accepted: 07/07/2020] [Indexed: 12/12/2022] Open
Abstract
Glial cells are key players in the proper formation and maintenance of the nervous system, thus contributing to neuronal health and disease in humans. However, little is known about the molecular pathways that govern glia-neuron communications in the diseased brain. Drosophila provides a useful in vivo model to explore the conserved molecular details of glial cell biology and their contributions to brain function and disease susceptibility. Herein, we review recent studies that explore glial functions in normal neuronal development, along with Drosophila models that seek to identify the pathological implications of glial defects in the context of various central nervous system disorders.
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Affiliation(s)
| | | | - Im-Soon Lee
- Department of Biological Sciences, Center for CHANS, Konkuk University, Seoul 05029, Korea; (T.K.); (B.S.)
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Ranganathan R, Haque S, Coley K, Shepheard S, Cooper-Knock J, Kirby J. Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia. Front Neurosci 2020; 14:684. [PMID: 32733193 PMCID: PMC7358438 DOI: 10.3389/fnins.2020.00684] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 06/04/2020] [Indexed: 12/11/2022] Open
Abstract
Amyotrophic lateral sclerosis and frontotemporal dementia are two progressive, adult onset neurodegenerative diseases, caused by the cell death of motor neurons in the motor cortex and spinal cord and cortical neurons in the frontal and temporal lobes, respectively. Whilst these have previously appeared to be quite distinct disorders, in terms of areas affected and clinical symptoms, identification of cognitive dysfunction as a component of amyotrophic lateral sclerosis (ALS), with some patients presenting with both ALS and FTD, overlapping features of neuropathology and the ongoing discoveries that a significant proportion of the genes underlying the familial forms of the disease are the same, has led to ALS and FTD being described as a disease spectrum. Many of these genes encode proteins in common biological pathways including RNA processing, autophagy, ubiquitin proteasome system, unfolded protein response and intracellular trafficking. This article provides an overview of the ALS-FTD genes before summarizing other known ALS and FTD causing genes where mutations have been found primarily in patients of one disease and rarely in the other. In discussing these genes, the review highlights the similarity of biological pathways in which the encoded proteins function and the interactions that occur between these proteins, whilst recognizing the distinctions of MAPT-related FTD and SOD1-related ALS. However, mutations in all of these genes result in similar pathology including protein aggregation and neuroinflammation, highlighting that multiple different mechanisms lead to common downstream effects and neuronal loss. Next generation sequencing has had a significant impact on the identification of genes associated with both diseases, and has also highlighted the widening clinical phenotypes associated with variants in these ALS and FTD genes. It is hoped that the large sequencing initiatives currently underway in ALS and FTD will begin to uncover why different diseases are associated with mutations within a single gene, especially as a personalized medicine approach to therapy, based on a patient's genetics, approaches the clinic.
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Affiliation(s)
- Ramya Ranganathan
- Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, Sheffield, United Kingdom
| | - Shaila Haque
- Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, Sheffield, United Kingdom
- Department of Biochemistry and Biotechnology, University of Barishal, Barishal, Bangladesh
| | - Kayesha Coley
- Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, Sheffield, United Kingdom
| | - Stephanie Shepheard
- Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, Sheffield, United Kingdom
| | - Johnathan Cooper-Knock
- Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, Sheffield, United Kingdom
| | - Janine Kirby
- Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, Sheffield, United Kingdom
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Foster AD, Rea SL. The role of sequestosome 1/p62 protein in amyotrophic lateral sclerosis and frontotemporal dementia pathogenesis. Neural Regen Res 2020; 15:2186-2194. [PMID: 32594029 PMCID: PMC7749485 DOI: 10.4103/1673-5374.284977] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are multifaceted diseases with genotypic, pathological and clinical overlap. One such overlap is the presence of SQSTM1/p62 mutations. While traditionally mutations manifesting in the ubiquitin-associated domain of p62 were associated with Paget’s disease of bone, mutations affecting all functional domains of p62 have now been identified in amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients. p62 is a multifunctional protein that facilitates protein degradation through autophagy and the ubiquitin-proteasome system, and also regulates cell survival via the Nrf2 antioxidant response pathway, the nuclear factor-kappa B signaling pathway and apoptosis. Dysfunction in these signaling and protein degradation pathways have been observed in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and mutations that affect the role of p62 in these pathways may contribute to disease pathogenesis. In this review we discuss the role of p62 in these pathways, the effects of p62 mutations and the effect of mutations in the p62 modulator TANK-binding kinase 1, in relation to amyotrophic lateral sclerosis-frontotemporal lobar degeneration pathogenesis.
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Affiliation(s)
- Adriana Delice Foster
- Harry Perkins Institute of Medical Research, University of Western Australia; Perron Institute for Neurological and Translational Science, Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Western Australia, Australia; Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Western Australia, Australia
| | - Sarah Lyn Rea
- Harry Perkins Institute of Medical Research, University of Western Australia; Perron Institute for Neurological and Translational Science, Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Western Australia, Australia; Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Western Australia, Australia
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Iacoangeli A, Al Khleifat A, Jones AR, Sproviero W, Shatunov A, Opie-Martin S, Morrison KE, Shaw PJ, Shaw CE, Fogh I, Dobson RJ, Newhouse SJ, Al-Chalabi A. C9orf72 intermediate expansions of 24-30 repeats are associated with ALS. Acta Neuropathol Commun 2019; 7:115. [PMID: 31315673 PMCID: PMC6637621 DOI: 10.1186/s40478-019-0724-4] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 04/16/2019] [Indexed: 12/11/2022] Open
Abstract
The expansion of a hexanucleotide repeat GGGGCC in C9orf72 is the most common known cause of ALS accounting for ~ 40% familial cases and ~ 7% sporadic cases in the European population. In most people, the repeat length is 2, but in people with ALS, hundreds to thousands of repeats may be observed. A small proportion of people have an intermediate expansion, of the order of 20 to 30 repeats in size, and it remains unknown whether intermediate expansions confer risk of ALS in the same way that massive expansions do. We investigated the association of this intermediate repeat with ALS by performing a meta-analysis of four previously published studies and a new British/Alzheimer's Disease Neuroimaging Initiative dataset of 1295 cases and 613 controls. The final dataset comprised 5071 cases and 3747 controls. Our meta-analysis showed association between ALS and intermediate C9orf72 repeats of 24 to 30 repeats in size (random-effects model OR = 4.2, 95% CI = 1.23-14.35, p-value = 0.02). Furthermore, we showed a different frequency of the repeat between the northern and southern European populations (Fisher's exact test p-value = 5 × 10- 3). Our findings provide evidence for the association between intermediate repeats and ALS (p-value = 2 × 10- 4) with direct relevance for research and clinical practice by showing that an expansion of 24 or more repeats should be considered pathogenic.
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Foster A, Scott D, Layfield R, Rea S. An FTLD-associated SQSTM1 variant impacts Nrf2 and NF-κB signalling and is associated with reduced phosphorylation of p62. Mol Cell Neurosci 2019; 98:32-45. [DOI: 10.1016/j.mcn.2019.04.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 03/28/2019] [Accepted: 04/02/2019] [Indexed: 12/12/2022] Open
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Burk K, Pasterkamp RJ. Disrupted neuronal trafficking in amyotrophic lateral sclerosis. Acta Neuropathol 2019; 137:859-877. [PMID: 30721407 PMCID: PMC6531423 DOI: 10.1007/s00401-019-01964-7] [Citation(s) in RCA: 118] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 01/19/2019] [Accepted: 01/19/2019] [Indexed: 02/07/2023]
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disease caused by degeneration of motor neurons in the brain and spinal cord leading to muscle weakness. Median survival after symptom onset in patients is 3-5 years and no effective therapies are available to treat or cure ALS. Therefore, further insight is needed into the molecular and cellular mechanisms that cause motor neuron degeneration and ALS. Different ALS disease mechanisms have been identified and recent evidence supports a prominent role for defects in intracellular transport. Several different ALS-causing gene mutations (e.g., in FUS, TDP-43, or C9ORF72) have been linked to defects in neuronal trafficking and a picture is emerging on how these defects may trigger disease. This review summarizes and discusses these recent findings. An overview of how endosomal and receptor trafficking are affected in ALS is followed by a description on dysregulated autophagy and ER/Golgi trafficking. Finally, changes in axonal transport and nucleocytoplasmic transport are discussed. Further insight into intracellular trafficking defects in ALS will deepen our understanding of ALS pathogenesis and will provide novel avenues for therapeutic intervention.
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Affiliation(s)
- Katja Burk
- Department of Neurologie, Universitätsmedizin Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
- Center for Biostructural Imaging of Neurodegeneration, Von-Siebold-Str. 3A, 37075, Göttingen, Germany.
| | - R Jeroen Pasterkamp
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.
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Mathis S, Goizet C, Soulages A, Vallat JM, Masson GL. Genetics of amyotrophic lateral sclerosis: A review. J Neurol Sci 2019; 399:217-226. [PMID: 30870681 DOI: 10.1016/j.jns.2019.02.030] [Citation(s) in RCA: 178] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 02/01/2019] [Accepted: 02/20/2019] [Indexed: 12/12/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of the motor pathways, invariably leading to death within a few years of onset. Most cases of ALS are sporadic, but familial forms of the disease (FALS) constitute 10% of the cases. Since the first identification of a causative gene in the 1990s and with recent advances in genetics, more than twenty genes have now been linked to FALS. This increased number of genes led to a tremendous amount of research, clearly contributed to a better understanding of the pathophysiology of this disorder, and paved the way for the development of new therapeutics and new hope for this fatal disease.
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Affiliation(s)
- Stéphane Mathis
- Department of Neurology, Nerve-Muscle Unit, CHU Bordeaux, (Pellegrin Hospital), University of Bordeaux, F-33000 Bordeaux, France; ALS Center, Nerve-Muscle Unit, CHU Bordeaux, (Pellegrin Hospital), University of Bordeaux, F-33000 Bordeaux, France.
| | - Cyril Goizet
- Department of Medical Genetics, 'Centre de Référence Maladies Rares Neurogénétique', CHU Bordeaux (Pellegrin Hospital), University of Bordeaux, 33000 Bordeaux, France; Laboratoire MRGM, INSERM U1211, F-33000 Bordeaux, France
| | - Antoine Soulages
- Department of Neurology, Nerve-Muscle Unit, CHU Bordeaux, (Pellegrin Hospital), University of Bordeaux, F-33000 Bordeaux, France
| | - Jean-Michel Vallat
- Department of Neurology, 'Centre de référence neuropathies rares', 2 avenue Martin Luther King, F-87000 Limoges, France
| | - Gwendal Le Masson
- Department of Neurology, Nerve-Muscle Unit, CHU Bordeaux, (Pellegrin Hospital), University of Bordeaux, F-33000 Bordeaux, France; Neurocentre Magendie, 'Physiopathologie de la Plasticité Neuronale', University of Bordeaux, U862, F-33000 Bordeaux, France; INSERM, Neurocentre Magendie, 'Physiopathologie de la Plasticité Neuronale', U862, F-33000 Bordeaux, France
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Campanari ML, Bourefis AR, Kabashi E. Diagnostic Challenge and Neuromuscular Junction Contribution to ALS Pathogenesis. Front Neurol 2019; 10:68. [PMID: 30787905 PMCID: PMC6372519 DOI: 10.3389/fneur.2019.00068] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 01/17/2019] [Indexed: 11/13/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) represents the major adult-onset motor neuron disease. Both human and animal studies reveal the critical implication of muscle and neuromuscular junctions (NMJs) in the initial phase of this disease. Despite the common efforts, ALS diagnosis remains particularly challenging since many other disorders can overlap yielding similar clinical phenotypic features. A combination of further research on the NMJ parameters that are specific for this disease and laboratory tests are crucial for the early determination of specific changes in the muscle, as well as in motor neuron and the prediction of ALS progression. Also, it could provide a powerful tool in the discrimination of particular ALS and ALS-mimic cases and increase the efficacy of therapeutic treatments.
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Affiliation(s)
- Maria-Letizia Campanari
- Sorbonne Université, Université Pierre et Marie Curie, Université de Paris 06, Unité Mixte 75, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 1127, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7225 Institut du Cerveau et de la Moelle Épinière, Paris, France.,Imagine Institute, INSERM Unité 1163, Paris Descartes Université, Paris, France
| | - Annis-Rayan Bourefis
- Sorbonne Université, Université Pierre et Marie Curie, Université de Paris 06, Unité Mixte 75, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 1127, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7225 Institut du Cerveau et de la Moelle Épinière, Paris, France.,Imagine Institute, INSERM Unité 1163, Paris Descartes Université, Paris, France
| | - Edor Kabashi
- Sorbonne Université, Université Pierre et Marie Curie, Université de Paris 06, Unité Mixte 75, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 1127, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7225 Institut du Cerveau et de la Moelle Épinière, Paris, France.,Imagine Institute, INSERM Unité 1163, Paris Descartes Université, Paris, France
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Molecular Mechanisms of Neurodegeneration Related to C9orf72 Hexanucleotide Repeat Expansion. Behav Neurol 2019; 2019:2909168. [PMID: 30774737 PMCID: PMC6350563 DOI: 10.1155/2019/2909168] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 08/28/2018] [Accepted: 09/18/2018] [Indexed: 12/11/2022] Open
Abstract
Two clinically distinct diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), have recently been classified as two extremes of the FTD/ALS spectrum. The neuropathological correlate of FTD is frontotemporal lobar degeneration (FTLD), characterized by tau-, TDP-43-, and FUS-immunoreactive neuronal inclusions. An earlier discovery that a hexanucleotide repeat expansion mutation in chromosome 9 open reading frame 72 (C9orf72) gene causes ALS and FTD established a special subtype of ALS and FTLD with TDP-43 pathology (C9FTD/ALS). Normal individuals carry 2–10 hexanucleotide GGGGCC repeats in the C9orf72 gene, while more than a few hundred repeats represent a risk for ALS and FTD. The proposed molecular mechanisms by which C9orf72 repeat expansions induce neurodegenerative changes are C9orf72 loss-of-function through haploinsufficiency, RNA toxic gain-of-function, and gain-of-function through the accumulation of toxic dipeptide repeat proteins. However, many more cellular processes are affected by pathological processes in C9FTD/ALS, including nucleocytoplasmic transport, RNA processing, normal function of nucleolus, formation of membraneless organelles, translation, ubiquitin proteasome system, Notch signalling pathway, granule transport, and normal function of TAR DNA-binding protein 43 (TDP-43). Although the exact molecular mechanisms through which C9orf72 repeat expansions account for neurodegeneration have not been elucidated, some potential therapeutics, such as antisense oligonucleotides targeting hexanucleotide GGGGCC repeats in mRNA, were successful in preclinical trials and are awaiting phase 1 clinical trials. In this review, we critically discuss each proposed mechanism and provide insight into the most recent studies aiming to elucidate the molecular underpinnings of C9FTD/ALS.
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43
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Pattamatta A, Cleary JD, Ranum LPW. All in the Family: Repeats and ALS/FTD. Trends Neurosci 2018; 41:247-250. [PMID: 29703376 DOI: 10.1016/j.tins.2018.03.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 03/08/2018] [Indexed: 12/12/2022]
Abstract
In 2011, an intronic (G4C2)•(G2C4) expansion was shown to cause the most common forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This discovery linked ALS with a clinically distinct form of dementia and a larger group of microsatellite repeat diseases, and catalyzed basic and translational research.
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Affiliation(s)
- Amrutha Pattamatta
- Center for Neurogenetics, College of Medicine, University of Florida, Gainesville, FL, USA; Departments of Molecular Genetics and Neurology, College of Medicine, University of Florida, Gainesville, FA, USA
| | - John D Cleary
- Center for Neurogenetics, College of Medicine, University of Florida, Gainesville, FL, USA; Departments of Molecular Genetics and Neurology, College of Medicine, University of Florida, Gainesville, FA, USA
| | - Laura P W Ranum
- Center for Neurogenetics, College of Medicine, University of Florida, Gainesville, FL, USA; Departments of Molecular Genetics and Neurology, College of Medicine, University of Florida, Gainesville, FA, USA; McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Genetics Institute, University of Florida, Gainesville, FL, USA.
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Iyer S, Subramanian V, Acharya KR. C9orf72, a protein associated with amyotrophic lateral sclerosis (ALS) is a guanine nucleotide exchange factor. PeerJ 2018; 6:e5815. [PMID: 30356970 PMCID: PMC6195791 DOI: 10.7717/peerj.5815] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 09/22/2018] [Indexed: 12/12/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two late onset neurodegenerative diseases, have been shown to share overlapping cellular pathologies and genetic origins. Studies suggest that a hexanucleotide repeat expansion in the first intron of the C9orf72 gene is the most common cause of familial FTD and ALS pathology. The C9orf72 protein is predicted to be a differentially expressed in normal and neoplastic cells domain protein implying that C9orf72 functions as a guanine nucleotide exchange factor (GEF) to regulate specific Rab GTPases. Reported studies thus far point to a putative role for C9orf72 in lysosome biogenesis, vesicular trafficking, autophagy and mechanistic target of rapamycin complex1 (mTORC1) signaling. Here we report the expression, purification and biochemical characterization of C9orf72 protein. We conclusively show that C9orf72 is a GEF. The distinctive presence of both Rab- and Rho-GTPase GEF activities suggests that C9orf72 may function as a dual exchange factor coupling physiological functions such as cytoskeleton modulation and autophagy with endocytosis.
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Affiliation(s)
- Shalini Iyer
- Department of Biology and Biochemistry, University of Bath, Bath, UK
| | | | - K Ravi Acharya
- Department of Biology and Biochemistry, University of Bath, Bath, UK
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Ebbert MTW, Farrugia SL, Sens JP, Jansen-West K, Gendron TF, Prudencio M, McLaughlin IJ, Bowman B, Seetin M, DeJesus-Hernandez M, Jackson J, Brown PH, Dickson DW, van Blitterswijk M, Rademakers R, Petrucelli L, Fryer JD. Long-read sequencing across the C9orf72 'GGGGCC' repeat expansion: implications for clinical use and genetic discovery efforts in human disease. Mol Neurodegener 2018; 13:46. [PMID: 30126445 PMCID: PMC6102925 DOI: 10.1186/s13024-018-0274-4] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 07/20/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Many neurodegenerative diseases are caused by nucleotide repeat expansions, but most expansions, like the C9orf72 'GGGGCC' (G4C2) repeat that causes approximately 5-7% of all amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases, are too long to sequence using short-read sequencing technologies. It is unclear whether long-read sequencing technologies can traverse these long, challenging repeat expansions. Here, we demonstrate that two long-read sequencing technologies, Pacific Biosciences' (PacBio) and Oxford Nanopore Technologies' (ONT), can sequence through disease-causing repeats cloned into plasmids, including the FTD/ALS-causing G4C2 repeat expansion. We also report the first long-read sequencing data characterizing the C9orf72 G4C2 repeat expansion at the nucleotide level in two symptomatic expansion carriers using PacBio whole-genome sequencing and a no-amplification (No-Amp) targeted approach based on CRISPR/Cas9. RESULTS Both the PacBio and ONT platforms successfully sequenced through the repeat expansions in plasmids. Throughput on the MinION was a challenge for whole-genome sequencing; we were unable to attain reads covering the human C9orf72 repeat expansion using 15 flow cells. We obtained 8× coverage across the C9orf72 locus using the PacBio Sequel, accurately reporting the unexpanded allele at eight repeats, and reading through the entire expansion with 1324 repeats (7941 nucleotides). Using the No-Amp targeted approach, we attained > 800× coverage and were able to identify the unexpanded allele, closely estimate expansion size, and assess nucleotide content in a single experiment. We estimate the individual's repeat region was > 99% G4C2 content, though we cannot rule out small interruptions. CONCLUSIONS Our findings indicate that long-read sequencing is well suited to characterizing known repeat expansions, and for discovering new disease-causing, disease-modifying, or risk-modifying repeat expansions that have gone undetected with conventional short-read sequencing. The PacBio No-Amp targeted approach may have future potential in clinical and genetic counseling environments. Larger and deeper long-read sequencing studies in C9orf72 expansion carriers will be important to determine heterogeneity and whether the repeats are interrupted by non-G4C2 content, potentially mitigating or modifying disease course or age of onset, as interruptions are known to do in other repeat-expansion disorders. These results have broad implications across all diseases where the genetic etiology remains unclear.
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Affiliation(s)
- Mark T. W. Ebbert
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224 USA
- Mayo Graduate School, Mayo Clinic, Rochester, MN 55905 USA
| | | | - Jonathon P. Sens
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224 USA
- Mayo Graduate School, Mayo Clinic, Rochester, MN 55905 USA
| | | | - Tania F. Gendron
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224 USA
| | | | | | | | | | | | - Jazmyne Jackson
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224 USA
| | | | | | | | - Rosa Rademakers
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224 USA
| | - Leonard Petrucelli
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224 USA
- Mayo Graduate School, Mayo Clinic, Rochester, MN 55905 USA
| | - John D. Fryer
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224 USA
- Mayo Graduate School, Mayo Clinic, Rochester, MN 55905 USA
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Abstract
Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease, affecting the upper and/or lower motor neurons. However, extramotor symptoms can also occur; cognitive deficits are present in more than 40% of patients and 5–8% of ALS patients develop frontotemporal dementia. There is no effective treatment for ALS and median survival is 2–3 years after onset. Amyotrophic lateral sclerosis is a genetically heterogeneous disorder with monogenic forms as well as complex genetic etiology. Currently, complex genetic risk factors are of minor interest for routine diagnostic testing or counseling of patients and their families. By contrast, a monogenic cause can be identified in 70% of familial and 10% of sporadic ALS cases. The most frequent genetic cause is a noncoding hexanucleotide repeat expansion in the C9orf72 gene. In recent years, high-throughput sequencing technologies have helped to identify additional monogenic and complex risk factors of ALS. Genetic counseling should be offered to all ALS patients and their first- and possibly second-degree relatives, and should include information about the possibilities and limitations of genetic testing. Routine diagnostic testing should at least encompass the most frequently mutated disease genes (C9orf72, SOD1, TDP-43, FUS). Targeted sequencing approaches including further disease genes may be applied. Caution is warranted as the C9orf72 repeat expansion cannot be detected by routine sequencing technologies and testing by polymerase chain reaction (PCR) is failure-prone. Predictive testing is possible in families in which a genetic cause has been identified, but the limitations of genetic testing (i. e., the problems of incomplete penetrance, variable expressivity and possible oligogenic inheritance) have to be explained to the families.
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47
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Revisiting the concept of amyotrophic lateral sclerosis as a multisystems disorder of limited phenotypic expression. Curr Opin Neurol 2018; 30:599-607. [PMID: 28914734 DOI: 10.1097/wco.0000000000000488] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE OF REVIEW The current review will examine the contemporary evidence that amyotrophic lateral sclerosis (ALS) is a syndrome in which the unifying feature is a progressive loss of upper and lower motor neuron function. RECENT FINDINGS Although ALS is traditionally viewed as a neurodegenerative disorder affecting the motor neurons, there is considerable phenotypic heterogeneity and widespread involvement of the central nervous system. A broad range of both causative and disease modifying genetic variants are associated with both sporadic and familial forms of ALS. A significant proportion of ALS patients have an associated frontotemporal dysfunction which can be a harbinger of a significantly shorter survival and for which there is increasing evidence of a fundamental disruption of tau metabolism in those affected individuals. Although the traditional neuropathology of the degenerating motor neurons in ALS is that of neuronal cytoplasmic inclusions composed neuronal intermediate filaments, the presence of neuronal cytoplasmic inclusions composed of RNA binding proteins suggests a key role for RNA dysmetabolism in the pathogenesis of ALS. SUMMARY ALS is a complex multisystem neurodegenerative syndrome with marked heterogeneity at not only the level of clinical expression, but also etiologically.
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Abstract
Repeat expansions in the promoter region of C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and related disorders of the ALS/frontotemporal lobar degeneration (FTLD) spectrum. Remarkable clinical heterogeneity among patients with a repeat expansion has been observed, and genetic anticipation over different generations has been suggested. Genetic factors modifying the clinical phenotype have been proposed, including genetic variation in other known disease genes, the genomic context of the C9orf72 repeat, and expanded repeat size, which has been estimated between 45 and several thousand units. The role of variability in normal and expanded repeat sizes for disease risk and clinical phenotype is under debate. Different pathogenic mechanisms have been proposed, including loss of function, RNA toxicity, and dipeptide repeat (DPR) protein toxicity resulting from abnormal translation of the expanded repeat, but the major mechanism is yet unclear.
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49
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Iyer S, Acharya KR, Subramanian V. A comparative bioinformatic analysis of C9orf72. PeerJ 2018; 6:e4391. [PMID: 29479499 PMCID: PMC5822839 DOI: 10.7717/peerj.4391] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 01/29/2018] [Indexed: 12/12/2022] Open
Abstract
C9orf72 is associated with frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS), both of which are devastating neurodegenerative diseases. Findings suggest that an expanded hexanucleotide repeat in the non-coding region of the C9orf72 gene is the most common cause of familial FTD and ALS. Despite considerable efforts being made towards discerning the possible disease-causing mechanism/s of this repeat expansion mutation, the biological function of C9orf72 remains unclear. Here, we present the first comprehensive genomic study on C9orf72 gene. Analysis of the genomic level organization of C9orf72 across select species revealed architectural similarity of syntenic regions between human and mouse but a lack of conservation of the repeat-harboring intron 1 sequence. Information generated in this study provides a broad genomic perspective of C9orf72 which would form a basis for subsequent experimental approaches and facilitate future mechanistic and functional studies on this gene.
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Affiliation(s)
- Shalini Iyer
- Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom
| | - K Ravi Acharya
- Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom
| | - Vasanta Subramanian
- Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom
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50
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Tosolini AP, Sleigh JN. Motor Neuron Gene Therapy: Lessons from Spinal Muscular Atrophy for Amyotrophic Lateral Sclerosis. Front Mol Neurosci 2017; 10:405. [PMID: 29270111 PMCID: PMC5725447 DOI: 10.3389/fnmol.2017.00405] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 11/21/2017] [Indexed: 12/11/2022] Open
Abstract
Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are severe nervous system diseases characterized by the degeneration of lower motor neurons. They share a number of additional pathological, cellular, and genetic parallels suggesting that mechanistic and clinical insights into one disorder may have value for the other. While there are currently no clinical ALS gene therapies, the splice-switching antisense oligonucleotide, nusinersen, was recently approved for SMA. This milestone was achieved through extensive pre-clinical research and patient trials, which together have spawned fundamental insights into motor neuron gene therapy. We have thus tried to distil key information garnered from SMA research, in the hope that it may stimulate a more directed approach to ALS gene therapy. Not only must the type of therapeutic (e.g., antisense oligonucleotide vs. viral vector) be sensibly selected, but considerable thought must be applied to the where, which, what, and when in order to enhance treatment benefit: to where (cell types and tissues) must the drug be delivered and how can this be best achieved? Which perturbed pathways must be corrected and can they be concurrently targeted? What dosing regime and concentration should be used? When should medication be administered? These questions are intuitive, but central to identifying and optimizing a successful gene therapy. Providing definitive solutions to these quandaries will be difficult, but clear thinking about therapeutic testing is necessary if we are to have the best chance of developing viable ALS gene therapies and improving upon early generation SMA treatments.
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Affiliation(s)
- Andrew P Tosolini
- Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, United Kingdom
| | - James N Sleigh
- Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, United Kingdom
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