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Eraña H, San Millán B, Díaz-Domínguez CM, Charco JM, Rodríguez R, Viéitez I, Pereda A, Yañez R, Geijo M, Navarro C, Perez de Nanclares G, Teijeira S, Castilla J. Description of the first Spanish case of Gerstmann-Sträussler-Scheinker disease with A117V variant: clinical, histopathological and biochemical characterization. J Neurol 2022; 269:4253-4263. [PMID: 35294616 PMCID: PMC9293843 DOI: 10.1007/s00415-022-11051-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 02/19/2022] [Accepted: 02/21/2022] [Indexed: 11/30/2022]
Abstract
Gerstmann–Sträussler–Scheinker disease (GSS) is a rare neurodegenerative illness that belongs to the group of hereditary or familial Transmissible Spongiform Encephalopathies (TSE). Due to the presence of different pathogenic alterations in the prion protein (PrP) coding gene, it shows an enhanced proneness to misfolding into its pathogenic isoform, leading to prion formation and propagation. This aberrantly folded protein is able to induce its conformation to the native counterparts forming amyloid fibrils and plaques partially resistant to protease degradation and showing neurotoxic properties. PrP with A117V pathogenic variant is the second most common genetic alteration leading to GSS and despite common phenotypic and neuropathological traits can be defined for each specific variant, strikingly heterogeneous manifestations have been reported for inter-familial cases bearing the same pathogenic variant or even within the same family. Given the scarcity of cases and their clinical, neuropathological, and biochemical variability, it is important to characterize thoroughly each reported case to establish potential correlations between clinical, neuropathological and biochemical hallmarks that could help to define disease subtypes. With that purpose in mind, this manuscript aims to provide a detailed report of the first Spanish GSS case associated with A117V variant including clinical, genetic, neuropathological and biochemical data, which could help define in the future potential disease subtypes and thus, explain the high heterogeneity observed in patients suffering from these maladies.
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Affiliation(s)
- Hasier Eraña
- Prion Research Lab, Basque Research and Technology Alliance (BRTA), Center for Cooperative Research in Biosciences (CIC BioGUNE), Derio, Spain
- Atlas Molecular Pharma S.L., Derio, Spain
| | - Beatriz San Millán
- Grupo de Enfermedades Raras y Medicina Pediátrica, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Vigo, Spain
| | - Carlos M Díaz-Domínguez
- Prion Research Lab, Basque Research and Technology Alliance (BRTA), Center for Cooperative Research in Biosciences (CIC BioGUNE), Derio, Spain
| | - Jorge M Charco
- Prion Research Lab, Basque Research and Technology Alliance (BRTA), Center for Cooperative Research in Biosciences (CIC BioGUNE), Derio, Spain
- Atlas Molecular Pharma S.L., Derio, Spain
| | - Rosa Rodríguez
- Servicio de Neurología, Complejo Hospitalario de Ourense, Ourense, Spain
| | - Irene Viéitez
- Grupo de Enfermedades Raras y Medicina Pediátrica, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Vigo, Spain
| | - Arrate Pereda
- Molecular (Epi)Genetics Laboratory, Araba University Hospital, Bioaraba Health Research Institute, Vitoria-Gasteiz, Spain
| | - Rosa Yañez
- Servicio de Neurología, Complejo Hospitalario de Ourense, Ourense, Spain
| | - Mariví Geijo
- Animal Health Department, NEIKER-Instituto Vasco de Investigación y Desarrollo Agrario, Basque Research and Technology Alliance (BRTA), Derio, Spain
| | - Carmen Navarro
- Grupo de Enfermedades Raras y Medicina Pediátrica, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Vigo, Spain
| | - Guiomar Perez de Nanclares
- Molecular (Epi)Genetics Laboratory, Araba University Hospital, Bioaraba Health Research Institute, Vitoria-Gasteiz, Spain
| | - Susana Teijeira
- Grupo de Enfermedades Raras y Medicina Pediátrica, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Vigo, Spain.
| | - Joaquín Castilla
- Prion Research Lab, Basque Research and Technology Alliance (BRTA), Center for Cooperative Research in Biosciences (CIC BioGUNE), Derio, Spain.
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Carlos III National Health Institute, Madrid, Spain.
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Jankovska N, Rusina R, Bruzova M, Parobkova E, Olejar T, Matej R. Human Prion Disorders: Review of the Current Literature and a Twenty-Year Experience of the National Surveillance Center in the Czech Republic. Diagnostics (Basel) 2021; 11:1821. [PMID: 34679519 PMCID: PMC8534461 DOI: 10.3390/diagnostics11101821] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/21/2021] [Accepted: 09/28/2021] [Indexed: 02/07/2023] Open
Abstract
Human prion disorders (transmissible spongiform encephalopathies, TSEs) are unique, progressive, and fatal neurodegenerative diseases caused by aggregation of misfolded prion protein in neuronal tissue. Due to the potential transmission, human TSEs are under active surveillance in a majority of countries; in the Czech Republic data are centralized at the National surveillance center (NRL) which has a clinical and a neuropathological subdivision. The aim of our article is to review current knowledge about human TSEs and summarize the experience of active surveillance of human prion diseases in the Czech Republic during the last 20 years. Possible or probable TSEs undergo a mandatory autopsy using a standardized protocol. From 2001 to 2020, 305 cases of sporadic and genetic TSEs including 8 rare cases of Gerstmann-Sträussler-Scheinker syndrome (GSS) were confirmed. Additionally, in the Czech Republic, brain samples from all corneal donors have been tested by the NRL immunology laboratory to increase the safety of corneal transplants since January 2007. All tested 6590 corneal donor brain tissue samples were negative for prion protein deposits. Moreover, the routine use of diagnostic criteria including biomarkers are robust enough, and not even the COVID-19 pandemic has negatively impacted TSEs surveillance in the Czech Republic.
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Affiliation(s)
- Nikol Jankovska
- Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University and Thomayer University Hospital, 14059 Prague, Czech Republic; (M.B.); (E.P.); (T.O.); (R.M.)
| | - Robert Rusina
- Department of Neurology, Third Faculty of Medicine, Charles University and Thomayer University Hospital, 14059 Prague, Czech Republic;
| | - Magdalena Bruzova
- Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University and Thomayer University Hospital, 14059 Prague, Czech Republic; (M.B.); (E.P.); (T.O.); (R.M.)
| | - Eva Parobkova
- Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University and Thomayer University Hospital, 14059 Prague, Czech Republic; (M.B.); (E.P.); (T.O.); (R.M.)
| | - Tomas Olejar
- Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University and Thomayer University Hospital, 14059 Prague, Czech Republic; (M.B.); (E.P.); (T.O.); (R.M.)
| | - Radoslav Matej
- Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University and Thomayer University Hospital, 14059 Prague, Czech Republic; (M.B.); (E.P.); (T.O.); (R.M.)
- Department of Pathology, First Faculty of Medicine, Charles University, and General University Hospital, 12800 Prague, Czech Republic
- Department of Pathology, Third Faculty of Medicine, Charles University, and University Hospital Kralovske Vinohrady, 10034 Prague, Czech Republic
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3
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Jankovska N, Olejar T, Matej R. Extracellular Amyloid Deposits in Alzheimer's and Creutzfeldt-Jakob Disease: Similar Behavior of Different Proteins? Int J Mol Sci 2020; 22:E7. [PMID: 33374972 PMCID: PMC7792617 DOI: 10.3390/ijms22010007] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/18/2020] [Accepted: 12/18/2020] [Indexed: 02/07/2023] Open
Abstract
Neurodegenerative diseases are characterized by the deposition of specific protein aggregates, both intracellularly and/or extracellularly, depending on the type of disease. The extracellular occurrence of tridimensional structures formed by amyloidogenic proteins defines Alzheimer's disease, in which plaques are composed of amyloid β-protein, while in prionoses, the same term "amyloid" refers to the amyloid prion protein. In this review, we focused on providing a detailed didactic description and differentiation of diffuse, neuritic, and burnt-out plaques found in Alzheimer's disease and kuru-like, florid, multicentric, and neuritic plaques in human transmissible spongiform encephalopathies, followed by a systematic classification of the morphological similarities and differences between the extracellular amyloid deposits in these disorders. Both conditions are accompanied by the extracellular deposits that share certain signs, including neuritic degeneration, suggesting a particular role for amyloid protein toxicity.
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Affiliation(s)
- Nikol Jankovska
- Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University and Thomayer Hospital, 100 00 Prague, Czech Republic; (T.O.); (R.M.)
| | - Tomas Olejar
- Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University and Thomayer Hospital, 100 00 Prague, Czech Republic; (T.O.); (R.M.)
| | - Radoslav Matej
- Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University and Thomayer Hospital, 100 00 Prague, Czech Republic; (T.O.); (R.M.)
- Department of Pathology, First Faculty of Medicine, Charles University, and General University Hospital, 100 00 Prague, Czech Republic
- Department of Pathology, Third Faculty of Medicine, Charles University, and University Hospital Kralovske Vinohrady, 100 00 Prague, Czech Republic
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Tanaka Y, Ikeda M, Mihara B, Ikeda Y, Sato K, Kitamoto T, Takao M. Importance of Neuropathological Diagnosis of Dementia Patients in Family Practice. JMA J 2019; 2:148-154. [PMID: 33615025 PMCID: PMC7889787 DOI: 10.31662/jmaj.2018-0060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 03/04/2019] [Indexed: 11/09/2022] Open
Abstract
Introduction: Creutzfeldt–Jakob disease (CJD) is an important dementia disorder. However, clinical diagnosis can be difficult and delayed for many primary physicians caring for dementia patients. The aim of the present study was to describe clinical and neuropathological results of an individual with CJD who was seen by a community hospital. Our report may inform many primary physicians on understanding the significance of CJD. Methods: Clinical information was obtained from medical records. Neuropathological and biochemical analyses were performed using autopsied brain. Results: A 58-year-old Japanese man who had worked as a carpenter developed memory and executive function impairments. He was initially diagnosed as having Alzheimer’s disease based on clinical and neuroradiological analyses. Myoclonus was observed in the later stage of clinical course. Hyperintense lesions on diffusion-weighted images were observed in the cerebral cortex in later stage. Analysis of cerebrospinal fluid showed increased levels of total tau and phospho-tau protein. However, 14-3-3 protein and amyloid β (1–42) were normal. Genetic analysis of the PRNP gene showed methionine homozygosity at codon 129 and glutamate homozygosity at codon 219. The results of neuropathological analysis were consistent with sporadic CJD (MM2 cortical type with some type 1 pattern of 3F4 immunoreactivity). Western blot analysis of the frontal and cerebellar cortex revealed a type 2 and type 1 pattern of proteinase K (PK)-resistant prion protein, respectively. No Alzheimer’s pathology was present. Conclusions: Our experience may help primary physicians to assess dementia patients. Since atypical forms of prion disease are now well-established, we need to consider prion disease in dementia patients. Clinical examination alone is not enough for dementia workup; thus, we must understand the importance of neuropathological study and encourage autopsy to reach a definite diagnosis of dementia.
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Affiliation(s)
- Yukiko Tanaka
- Department of Internal Medicine, Medical Corporation Taiseikai, Uchida Hospital, Gunma, Japan
| | - Masaki Ikeda
- Department of Neurology, Gunma University Graduate School of Medicine, Gunma, Japan
| | | | - Yoshio Ikeda
- Department of Neurology, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Katsuya Sato
- Department of Locomotive Rehabilitation Science, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tetsuyuki Kitamoto
- Department of Neurological Sciences, Tohoku University, Graduate School of Medicine, Miyagi, Japan
| | - Masaki Takao
- Mihara Memorial Hospital, Gunma, Japan.,Department of Neurology, Saitama Medical University International Medical Center, Saitama, Japan
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Kovacs GG. Molecular pathology of neurodegenerative diseases: principles and practice. J Clin Pathol 2019; 72:725-735. [PMID: 31395625 DOI: 10.1136/jclinpath-2019-205952] [Citation(s) in RCA: 128] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 07/25/2019] [Accepted: 07/26/2019] [Indexed: 12/12/2022]
Abstract
Neurodegenerative diseases are characterised by selective dysfunction and progressive loss of synapses and neurons associated with pathologically altered proteins that deposit primarily in the human brain and spinal cord. Recent discoveries have identified a spectrum of distinct immunohistochemically and biochemically detectable proteins, which serve as a basis for protein-based disease classification. Diagnostic criteria have been updated and disease staging procedures have been proposed. These are based on novel concepts which recognise that (1) most of these proteins follow a sequential distribution pattern in the brain suggesting a seeding mechanism and cell-to-cell propagation; (2) some of the neurodegeneration-associated proteins can be detected in peripheral organs; and (3) concomitant presence of neurodegeneration-associated proteins is more the rule than the exception. These concepts, together with the fact that the clinical symptoms do not unequivocally reflect the molecular pathological background, place the neuropathological examination at the centre of requirements for an accurate diagnosis. The need for quality control in biomarker development, clinical and neuroimaging studies, and evaluation of therapy trials, as well as an increasing demand for the general public to better understand human brain disorders, underlines the importance for a renaissance of postmortem neuropathological studies at this time. This review summarises recent advances in neuropathological diagnosis and reports novel aspects of relevance for general pathological practice.
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Affiliation(s)
- Gabor G Kovacs
- Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada
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Zhao MM, Feng LS, Hou S, Shen PP, Cui L, Feng JC. Gerstmann-Sträussler-Scheinker disease: A case report. World J Clin Cases 2019; 7:389-395. [PMID: 30746381 PMCID: PMC6369391 DOI: 10.12998/wjcc.v7.i3.389] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 12/24/2018] [Accepted: 12/30/2018] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Gerstmann-Sträussler-Scheinker (GSS) disease is an inherited prion disease that is clinically characterized by the early onset of progressive cerebellar ataxia. The incidence of GSS is extremely low and it is particularly rare in China. Therefore, clinicians may easily confuse this disease with other diseases that also cause ataxia, resulting in its under-diagnosis or misdiagnosis.
CASE SUMMARY Here, we report the first case of genetically diagnosed GSS disease in Northeast China. The patient exhibited typical ataxia and dysarthria 2.5 years after symptom onset. However, magnetic resonance imaging of the brain and spinal cord revealed a normal anatomy. Screening results for the spinocerebellar ataxia gene were also negative. We thus proposed to expand the scope of genetic screening to include over 200 mutations that can cause ataxia. A final diagnosis of GSS was presented and the patient was followed for more than 3.5 years, during which we noted imaging abnormalities. The patient gradually exhibited decorticate posturing and convulsions. We recommended administration of oral sodium valproate, which resolved the convulsions.
CONCLUSION Patients with inherited ataxia should be considered for a diagnosis of GSS via genetic testing at an early disease stage.
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Affiliation(s)
- Ming-Ming Zhao
- Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Liang-Shu Feng
- Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Shuai Hou
- Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Ping-Ping Shen
- Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li Cui
- Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Jia-Chun Feng
- Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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7
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Di Fede G, Catania M, Atzori C, Moda F, Pasquali C, Indaco A, Grisoli M, Zuffi M, Guaita MC, Testi R, Taraglio S, Sessa M, Gusmaroli G, Spinelli M, Salzano G, Legname G, Tarletti R, Godi L, Pocchiari M, Tagliavini F, Imperiale D, Giaccone G. Clinical and neuropathological phenotype associated with the novel V189I mutation in the prion protein gene. Acta Neuropathol Commun 2019; 7:1. [PMID: 30606247 PMCID: PMC6317215 DOI: 10.1186/s40478-018-0656-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 12/21/2018] [Indexed: 12/29/2022] Open
Abstract
Prion diseases are neurodegenerative disorders which are caused by an accumulation of the abnormal, misfolded prion protein known as scrapie prion protein (PrPSc). These disorders are unique as they occur as sporadic, genetic and acquired forms. Sporadic Creutzfeldt-Jakob Disease (CJD) is the most common human prion disease, accounting for approximately 85-90% of cases, whereas autosomal dominant genetic forms, due to mutations in the prion protein gene (PRNP), account for 10-15% of cases. Genetic forms show a striking variability in their clinical and neuropathological picture and can sometimes mimic other neurodegenerative diseases.We report a novel PRNP mutation (V189I) in four CJD patients from three unrelated pedigrees. In three patients, the clinical features were typical for CJD and the diagnosis was pathologically confirmed, while the fourth patient presented with a complex phenotype including rapidly progressive dementia, behavioral abnormalities, ataxia and extrapyramidal features, and the diagnosis was probable CJD by current criteria, on the basis of PrPSc detection in CSF by Real Time Quaking-Induced Conversion assay. In all the three patients with autopsy findings, the neuropathological analysis revealed diffuse synaptic type deposition of proteinase K-resistant prion protein (PrPres), and type 1 PrPres was identified in the brain by western blot analysis. So, the histopathological and biochemical profile associated with the V189I mutation was indistinguishable from the MM1/MV1 subtype of sporadic CJD.Our findings support a pathogenic role for the V189I PRNP variant, confirm the heterogeneity of the clinical phenotypes associated to PRNP mutations and highlight the importance of PrPSc detection assays as diagnostic tools to unveil prion diseases presenting with atypical phenotypes.
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Affiliation(s)
- Giuseppe Di Fede
- Neurology V - Neuropathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy.
| | - Marcella Catania
- Neurology V - Neuropathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy
| | - Cristiana Atzori
- Centro Regionale Malattie da Prioni (DOMP), ASL 'Città di Torino', Turin, Italy
| | - Fabio Moda
- Neurology V - Neuropathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy
| | - Claudio Pasquali
- Neurology V - Neuropathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy
| | - Antonio Indaco
- Neurology V - Neuropathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy
| | - Marina Grisoli
- Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Marta Zuffi
- Neurology Unit, Multimedica, Castellanza, Italy
| | | | - Roberto Testi
- Centro Regionale Malattie da Prioni (DOMP), ASL 'Città di Torino', Turin, Italy
| | - Stefano Taraglio
- Centro Regionale Malattie da Prioni (DOMP), ASL 'Città di Torino', Turin, Italy
| | - Maria Sessa
- Neurology Unit, Foundation IRCCS Centro s. Raffaele del Monte Tabor, Milan, Italy
- Neurology Unit - ASST Cremona, Cremona, Italy
| | | | | | - Giulia Salzano
- Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy
| | - Giuseppe Legname
- Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy
| | | | - Laura Godi
- Neurology Unit, ASL Novara, Ospedale di Borgomanero, Borgomanero, Italy
| | | | - Fabrizio Tagliavini
- Scientific Directorate, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Daniele Imperiale
- Centro Regionale Malattie da Prioni (DOMP), ASL 'Città di Torino', Turin, Italy
| | - Giorgio Giaccone
- Neurology V - Neuropathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy
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8
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Capellari S, Baiardi S, Rinaldi R, Bartoletti-Stella A, Graziano C, Piras S, Calandra-Buonaura G, D'Angelo R, Terziotti C, Lodi R, Donadio V, Pironi L, Cortelli P, Parchi P. Two novel PRNP truncating mutations broaden the spectrum of prion amyloidosis. Ann Clin Transl Neurol 2018; 5:777-783. [PMID: 29928661 PMCID: PMC5989776 DOI: 10.1002/acn3.568] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 03/25/2018] [Accepted: 03/28/2018] [Indexed: 12/23/2022] Open
Abstract
Truncating mutations in PRNP have been associated with heterogeneous phenotypes ranging from chronic diarrhea and neuropathy to dementia, either rapidly or slowly progressive. We identified novel PRNP stop‐codon mutations (p.Y163X, p.Y169X) in two Italian kindreds. Disease typically presented in the third or fourth decade with progressive autonomic failure and diarrhea. Moreover, one proband (p.Y163X) developed late cognitive decline, whereas some of his relatives presented with isolated cognitive and psychiatric symptoms. Our results strengthen the link between PRNP truncating mutations and systemic abnormal PrP deposition and support a wider application of PRNP screening to include unsolved cases of familial autonomic neuropathy.
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Affiliation(s)
- Sabina Capellari
- Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy.,Institute of Neurological Sciences IRCCS Bologna Italy
| | - Simone Baiardi
- Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy
| | - Rita Rinaldi
- Neurology Unit S. Orsola-Malpighi University Hospital Bologna Italy
| | - Anna Bartoletti-Stella
- Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy.,Institute of Neurological Sciences IRCCS Bologna Italy
| | - Claudio Graziano
- Medical Genetics Unit S. Orsola-Malpighi University Hospital Bologna Italy
| | - Silvia Piras
- Institute of Neurological Sciences IRCCS Bologna Italy
| | - Giovanna Calandra-Buonaura
- Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy.,Institute of Neurological Sciences IRCCS Bologna Italy
| | - Roberto D'Angelo
- Neurology Unit S. Orsola-Malpighi University Hospital Bologna Italy
| | | | - Raffaele Lodi
- Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy.,Functional MR Unit S. Orsola-Malpighi University Hospital Bologna Italy
| | | | - Loris Pironi
- Chronic Intestinal Failure Center S. Orsola-Malpighi University Hospital Bologna Italy
| | - Pietro Cortelli
- Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy.,Institute of Neurological Sciences IRCCS Bologna Italy
| | - Piero Parchi
- Institute of Neurological Sciences IRCCS Bologna Italy.,Department of Experimental Diagnostic and Specialty Medicine (DIMES) University of Bologna Bologna Italy
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9
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Abstract
Genetic Creutzfeldt-Jakob disease (CJD) is associated with mutations in the human PrP gene (PRNP) on chromosome 20p12-pter. Pathogenic mutations have been identified in 10-15% of all CJD patients, who often have a family history of autosomal-dominant pattern of inheritance and variable penetrance. However, the use of genetic tests implemented by surveillance networks all over the world increasingly identifies unexpectedly PRNP mutations in persons apparently presenting with a sporadic form of CJD. A high phenotypic variability was reported in genetic prion diseases, which partly overlap with the features of sporadic CJD. Here we review recent advances on the epidemiologic, clinical, and neuropathologic features of cases that phenotypically resemble CJD linked to point and insert mutations of the PRNP gene. Multidisciplinary studies are still required to understand the phenotypic spectrum, penetrance, and significance of PRNP mutations.
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10
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Charco JM, Eraña H, Venegas V, García-Martínez S, López-Moreno R, González-Miranda E, Pérez-Castro MÁ, Castilla J. Recombinant PrP and Its Contribution to Research on Transmissible Spongiform Encephalopathies. Pathogens 2017; 6:E67. [PMID: 29240682 PMCID: PMC5750591 DOI: 10.3390/pathogens6040067] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Revised: 12/08/2017] [Accepted: 12/12/2017] [Indexed: 01/13/2023] Open
Abstract
The misfolding of the cellular prion protein (PrPC) into the disease-associated isoform (PrPSc) and its accumulation as amyloid fibrils in the central nervous system is one of the central events in transmissible spongiform encephalopathies (TSEs). Due to the proteinaceous nature of the causal agent the molecular mechanisms of misfolding, interspecies transmission, neurotoxicity and strain phenomenon remain mostly ill-defined or unknown. Significant advances were made using in vivo and in cellula models, but the limitations of these, primarily due to their inherent complexity and the small amounts of PrPSc that can be obtained, gave rise to the necessity of new model systems. The production of recombinant PrP using E. coli and subsequent induction of misfolding to the aberrant isoform using different techniques paved the way for the development of cell-free systems that complement the previous models. The generation of the first infectious recombinant prion proteins with identical properties of brain-derived PrPSc increased the value of cell-free systems for research on TSEs. The versatility and ease of implementation of these models have made them invaluable for the study of the molecular mechanisms of prion formation and propagation, and have enabled improvements in diagnosis, high-throughput screening of putative anti-prion compounds and the design of novel therapeutic strategies. Here, we provide an overview of the resultant advances in the prion field due to the development of recombinant PrP and its use in cell-free systems.
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Affiliation(s)
- Jorge M. Charco
- CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160 Derio, Spain; (J.M.C.); (H.E.); (V.V.); (S.G.-M.); (R.L.-M.); (E.G.-M.); (M.Á.P.-C.)
| | - Hasier Eraña
- CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160 Derio, Spain; (J.M.C.); (H.E.); (V.V.); (S.G.-M.); (R.L.-M.); (E.G.-M.); (M.Á.P.-C.)
| | - Vanessa Venegas
- CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160 Derio, Spain; (J.M.C.); (H.E.); (V.V.); (S.G.-M.); (R.L.-M.); (E.G.-M.); (M.Á.P.-C.)
| | - Sandra García-Martínez
- CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160 Derio, Spain; (J.M.C.); (H.E.); (V.V.); (S.G.-M.); (R.L.-M.); (E.G.-M.); (M.Á.P.-C.)
| | - Rafael López-Moreno
- CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160 Derio, Spain; (J.M.C.); (H.E.); (V.V.); (S.G.-M.); (R.L.-M.); (E.G.-M.); (M.Á.P.-C.)
| | - Ezequiel González-Miranda
- CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160 Derio, Spain; (J.M.C.); (H.E.); (V.V.); (S.G.-M.); (R.L.-M.); (E.G.-M.); (M.Á.P.-C.)
| | - Miguel Ángel Pérez-Castro
- CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160 Derio, Spain; (J.M.C.); (H.E.); (V.V.); (S.G.-M.); (R.L.-M.); (E.G.-M.); (M.Á.P.-C.)
| | - Joaquín Castilla
- CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160 Derio, Spain; (J.M.C.); (H.E.); (V.V.); (S.G.-M.); (R.L.-M.); (E.G.-M.); (M.Á.P.-C.)
- IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
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11
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Nonno R, Angelo Di Bari M, Agrimi U, Pirisinu L. Transmissibility of Gerstmann-Sträussler-Scheinker syndrome in rodent models: New insights into the molecular underpinnings of prion infectivity. Prion 2017; 10:421-433. [PMID: 27892798 PMCID: PMC5161296 DOI: 10.1080/19336896.2016.1239686] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Prion diseases, or transmissible spongiform encephalopathies, have revealed the bewildering phenomenon of transmissibility in neurodegenerative diseases. Hence, the experimental transmissibility of prion-like neurodegenerative diseases via template directed misfolding has become the focus of intense research. Gerstmann-Sträussler-Scheinker disease (GSS) is an inherited prion disease associated with mutations in the prion protein gene. However, with the exception of a few GSS cases with P102L mutation characterized by co-accumulation of protease-resistant PrP core (PrPres) of ∼21 kDa, attempts to transmit to rodents GSS associated to atypical misfolded prion protein with ∼8 kDa PrPres have been unsuccessful. As a result, these GSS subtypes have often been considered as non-transmissible proteinopathies rather than true prion diseases. In a recent study we inoculated bank voles with GSS cases associated with P102L, A117V and F198S mutations and found that they transmitted efficiently and produced distinct pathological phenotypes, irrespective of the presence of 21 kDa PrPres in the inoculum. This study demonstrates that GSS is a genuine prion disease characterized by both transmissibility and strain variation. We discuss the implications of these findings for the understanding of the heterogeneous clinic-pathological phenotypes of GSS and of the molecular underpinnings of prion infectivity.
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Affiliation(s)
- Romolo Nonno
- a Department of Veterinary Public Health and Food Safety , Istituto Superiore di Sanità , Rome , Italy
| | - Michele Angelo Di Bari
- a Department of Veterinary Public Health and Food Safety , Istituto Superiore di Sanità , Rome , Italy
| | - Umberto Agrimi
- a Department of Veterinary Public Health and Food Safety , Istituto Superiore di Sanità , Rome , Italy
| | - Laura Pirisinu
- a Department of Veterinary Public Health and Food Safety , Istituto Superiore di Sanità , Rome , Italy
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12
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Abstract
The chapter describes the epidemiology of cerebrovascular diseases, anatomy of the cerebral blood vessels, pathophysiology of ischemia, hypoxia, hypoxemia, anemic hypoxia, histotoxic hypoxia, carbon monoxide damage, hyperoxid brain damage and decompression sickness, and selective cell and regional vulnerability; diseases of the blood vessels including atherosclerosis, hypertensive angiopathy, small vessel disease, inflammatory vascular diseases, cerebral amyloid angiopathies, CADASIL, CARASIL and other diseases that can lead to cerebrovascular occlusion; intracranial and intraspinal aneurysms and vascular malformations; hematologic disorders that can cause cerebral infarct or hemorrhage; brain ischemic damage; and spontaneous intracranial bleeding. Within ischemic brain damage, focal cerebral ischemia, hemorrhagic infarct, brain edema, penumbra, global cerebral ischemia, venous thrombosis, lacunas and lacunar state, status cribosus, granular atrophy of the cerebral cortex, hippocampal sclerosis, vascular leukoencephalopathy Binswanger type and multi-infarct encephalopathy are discussed in detail. Cognitive impairment of vascular origin deserves an individual section.
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Affiliation(s)
- Isidro Ferrer
- Pathologic Anatomy Service, Institute of Neuropathology, Bellvitge University Hospital, University of Barcelona, Barcelona, Spain.
| | - Noemi Vidal
- Pathologic Anatomy Service, Institute of Neuropathology, Bellvitge University Hospital, University of Barcelona, Barcelona, Spain
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13
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Arendt T, Stieler JT, Holzer M. Tau and tauopathies. Brain Res Bull 2016; 126:238-292. [PMID: 27615390 DOI: 10.1016/j.brainresbull.2016.08.018] [Citation(s) in RCA: 429] [Impact Index Per Article: 47.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 08/31/2016] [Accepted: 08/31/2016] [Indexed: 12/11/2022]
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14
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Kovacs GG, Rahimi J, Ströbel T, Lutz MI, Regelsberger G, Streichenberger N, Perret-Liaudet A, Höftberger R, Liberski PP, Budka H, Sikorska B. Tau pathology in Creutzfeldt-Jakob disease revisited. Brain Pathol 2016; 27:332-344. [PMID: 27377321 PMCID: PMC8028936 DOI: 10.1111/bpa.12411] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 06/17/2016] [Indexed: 01/05/2023] Open
Abstract
Creutzfeldt-Jakob disease (CJD) is a human prion disease with different etiologies. To determine the spectrum of tau pathologies in CJD, we assessed phospho-Tau (pTau) immunoreactivities in 75 sporadic CJD cases including an evaluation of the entorhinal cortex and six hippocampal subregions. Twelve cases (16%) showed only small tau-immunoreactive neuritic profiles. Fifty-two (69.3%) showed additional tau pathology in the medial temporal lobe compatible with primary age related tauopathy (PART). In 22/52 cases the lower pTau immunoreactivity load in the entorhinal cortex as compared to subiculum, dentate gyrus or CA4 region of the hippocampus was significantly different from the typical distribution of the Braak staging. A further 11 cases (14.7%) showed widespread tau pathologies compatible with features of primary tauopathies or the gray matter type of ageing-related tau astrogliopathy (ARTAG). Prominent gray matter ARTAG was also observed in two out of three additionally examined V203I genetic CJD cases. Analysis of cerebrospinal fluid revealed prominent increase of total tau protein in cases with widespread tau pathology, while pTau (T181) level was increased only in four. This correlated with immunohistochemical observations showing less pathology with anti-pTau T181 antibody when compared to anti-pTau S202/T205, T212/S214 and T231. The frequency of tau pathologies is not unusually high in sporadic CJD and does not precisely relate to PrP deposition. However, the pattern of hippocampal tau pathology often deviates from the stages of Braak. Currently applied examination of cerebrospinal fluid pTau (T181) level does not reliably reflect primary tauopathies, PART and ARTAG seen in CJD brains.
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Affiliation(s)
- Gabor G Kovacs
- Institute of Neurology, Medical University of Vienna, and Austrian Reference Center for Human Prion Diseases, Vienna, Austria
| | - Jasmin Rahimi
- Institute of Neurology, Medical University of Vienna, and Austrian Reference Center for Human Prion Diseases, Vienna, Austria
| | - Thomas Ströbel
- Institute of Neurology, Medical University of Vienna, and Austrian Reference Center for Human Prion Diseases, Vienna, Austria
| | - Mirjam I Lutz
- Institute of Neurology, Medical University of Vienna, and Austrian Reference Center for Human Prion Diseases, Vienna, Austria
| | - Günther Regelsberger
- Institute of Neurology, Medical University of Vienna, and Austrian Reference Center for Human Prion Diseases, Vienna, Austria
| | - Nathalie Streichenberger
- Prion Disease Laboratory, Pathology and Biochemistry, Groupement Hospitalier Est, Hospices Civils de Lyon/Claude Bernard University, Lyon, France.,Institut NeuroMyogène CNRS UMR 5310 - INSERM U1217, Lyon, France
| | - Armand Perret-Liaudet
- Prion Disease Laboratory, Pathology and Biochemistry, Groupement Hospitalier Est, Hospices Civils de Lyon/Claude Bernard University, Lyon, France.,Centre de Recherche en Neurosciences de Lyon (Laboratoire BioRaN), Université Claude Bernard Lyon 1 - CNRS UMR5292 - INSERM U1028, Lyon, France
| | - Romana Höftberger
- Institute of Neurology, Medical University of Vienna, and Austrian Reference Center for Human Prion Diseases, Vienna, Austria
| | - Pawel P Liberski
- Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland
| | - Herbert Budka
- Institute of Neurology, Medical University of Vienna, and Austrian Reference Center for Human Prion Diseases, Vienna, Austria.,Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland
| | - Beata Sikorska
- Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland
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15
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Umeh CC, Kalakoti P, Greenberg MK, Notari S, Cohen Y, Gambetti P, Oblak AL, Ghetti B, Mari Z. Clinicopathological Correlates in a PRNP P102L Mutation Carrier with Rapidly Progressing Parkinsonism-dystonia. Mov Disord Clin Pract 2016; 3:355-358. [PMID: 27617269 PMCID: PMC5015693 DOI: 10.1002/mdc3.12307] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Revised: 11/05/2015] [Accepted: 11/07/2015] [Indexed: 01/02/2023] Open
Abstract
Parkinsonism-dystonia is rare in carriers of PRNP P102L mutation. Severity and distribution of prion protein (PrP) deposition may influence the clinical presentation. We present such clinic-pathological correlation in a 56-year-old male with a PRNP P102L mutation associated with a phenotype characterized by rapidly progressing parkinsonism-dystonia. The patient was studied clinically (videotaped exams, brain MRIs); molecular genetically (gene sequence analysis); and neuropathologically (histology, immunohistochemistry) during his 7-month disease course. The patient had parkinsonism, apraxia, aphasia, and dystonia, which progressed rapidly. Molecular genetic analysis revealed PRNP P102L mutation carrier status. Brain MRIs revealed progressive global volume loss and T2/FLAIR hyperintensity in neocortex and basal ganglia. Postmortem examination showed neuronal loss, gliosis, spongiform changes, and PrP deposition in the striatum. PrP immunohistochemistry revealed widespread severe PrP deposition in the thalamus and cerebellar cortex. Based on the neuropathological and molecular-genetic analysis, the rapidly progressing parkinsonism-dystonia correlated with nigrostriatal, thalamic, and cerebellar pathology.
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Affiliation(s)
- Chizoba C. Umeh
- Department of NeurologyJohns Hopkins School of MedicineBaltimoreMarylandUSA
| | - Piyush Kalakoti
- Department of NeurologyJohns Hopkins School of MedicineBaltimoreMarylandUSA
| | | | - Silvio Notari
- National Prion Disease Pathology Surveillance CenterCase Western Reserve UniversityClevelandOhioUSA
| | - Yvonne Cohen
- National Prion Disease Pathology Surveillance CenterCase Western Reserve UniversityClevelandOhioUSA
| | - Pierluigi Gambetti
- National Prion Disease Pathology Surveillance CenterCase Western Reserve UniversityClevelandOhioUSA
| | - Adrian L. Oblak
- Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisIndianaUSA
| | - Bernardino Ghetti
- Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisIndianaUSA
| | - Zoltan Mari
- Department of NeurologyJohns Hopkins School of MedicineBaltimoreMarylandUSA
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16
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Pirisinu L, Di Bari MA, D'Agostino C, Marcon S, Riccardi G, Poleggi A, Cohen ML, Appleby BS, Gambetti P, Ghetti B, Agrimi U, Nonno R. Gerstmann-Sträussler-Scheinker disease subtypes efficiently transmit in bank voles as genuine prion diseases. Sci Rep 2016; 6:20443. [PMID: 26841849 PMCID: PMC4740801 DOI: 10.1038/srep20443] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 01/04/2016] [Indexed: 11/16/2022] Open
Abstract
Gerstmann-Sträussler-Scheinker disease (GSS) is an inherited neurodegenerative disorder associated with mutations in the prion protein gene and accumulation of misfolded PrP with protease-resistant fragments (PrPres) of 6–8 kDa. With the exception of a few GSS cases characterized by co-accumulation of PrPres of 21 kDa, efforts to transmit GSS to rodents have been unsuccessful. As a result, GSS subtypes exclusively associated with 6–8 kDa PrPres have often been considered as non-transmissible proteinopathies rather than true prion diseases. We show that GSS with P102L, A117V and F198S mutations transmit efficiently and produce distinct pathological phenotypes in bank voles (M. glareolus), irrespective of the presence of 21 kDa PrPres in the inoculum, demonstrating that GSS is a genuine prion disease characterized by both transmissibility and strain variation.
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Affiliation(s)
- Laura Pirisinu
- Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Michele A Di Bari
- Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Claudia D'Agostino
- Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Stefano Marcon
- Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Geraldina Riccardi
- Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Anna Poleggi
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Mark L Cohen
- Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, School of Medicine, 2085 Adelbert Road Cleveland, Ohio, OH 44106, USA
| | - Brian S Appleby
- Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, School of Medicine, 2085 Adelbert Road Cleveland, Ohio, OH 44106, USA
| | - Pierluigi Gambetti
- Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, School of Medicine, 2085 Adelbert Road Cleveland, Ohio, OH 44106, USA
| | - Bernardino Ghetti
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Umberto Agrimi
- Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Romolo Nonno
- Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
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17
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Kovacs GG. Molecular Pathological Classification of Neurodegenerative Diseases: Turning towards Precision Medicine. Int J Mol Sci 2016; 17:ijms17020189. [PMID: 26848654 PMCID: PMC4783923 DOI: 10.3390/ijms17020189] [Citation(s) in RCA: 198] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 01/21/2016] [Accepted: 01/26/2016] [Indexed: 02/06/2023] Open
Abstract
Neurodegenerative diseases (NDDs) are characterized by selective dysfunction and loss of neurons associated with pathologically altered proteins that deposit in the human brain but also in peripheral organs. These proteins and their biochemical modifications can be potentially targeted for therapy or used as biomarkers. Despite a plethora of modifications demonstrated for different neurodegeneration-related proteins, such as amyloid-β, prion protein, tau, α-synuclein, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma protein (FUS), molecular classification of NDDs relies on detailed morphological evaluation of protein deposits, their distribution in the brain, and their correlation to clinical symptoms together with specific genetic alterations. A further facet of the neuropathology-based classification is the fact that many protein deposits show a hierarchical involvement of brain regions. This has been shown for Alzheimer and Parkinson disease and some forms of tauopathies and TDP-43 proteinopathies. The present paper aims to summarize current molecular classification of NDDs, focusing on the most relevant biochemical and morphological aspects. Since the combination of proteinopathies is frequent, definition of novel clusters of patients with NDDs needs to be considered in the era of precision medicine. Optimally, neuropathological categorizing of NDDs should be translated into in vivo detectable biomarkers to support better prediction of prognosis and stratification of patients for therapy trials.
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Affiliation(s)
- Gabor G Kovacs
- Institute of Neurology, Medical University of Vienna, AKH 4J, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
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18
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Kovacs GG. Invited review: Neuropathology of tauopathies: principles and practice. Neuropathol Appl Neurobiol 2015; 41:3-23. [PMID: 25495175 DOI: 10.1111/nan.12208] [Citation(s) in RCA: 374] [Impact Index Per Article: 37.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 12/09/2014] [Indexed: 12/11/2022]
Abstract
Tauopathies are clinically, morphologically and biochemically heterogeneous neurodegenerative diseases characterized by the deposition of abnormal tau protein in the brain. The neuropathological phenotypes are distinguished based on the involvement of different anatomical areas, cell types and presence of distinct isoforms of tau in the pathological deposits. The nomenclature of primary tauopathies overlaps with the modern classification of frontotemporal lobar degeneration. Neuropathological phenotypes comprise Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, formerly called also as neurofibrillary tangle-only dementia, and a recently characterized entity called globular glial tauopathy. Mutations in the gene encoding the microtubule-associated protein tau are associated with frontotemporal dementia and parkinsonism linked to chromosome 17. In addition, further neurodegenerative conditions with diverse aetiologies may be associated with tau pathologies. Thus, the spectrum of tau pathologies and tauopathy entities expands beyond the traditionally discussed disease forms. Detailed multidisciplinary studies are still required to understand their significance.
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Affiliation(s)
- G G Kovacs
- Institute of Neurology, Medical University of Vienna, Vienna, Austria
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19
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Murali A, Maue RA, Dolph PJ. Reversible symptoms and clearance of mutant prion protein in an inducible model of a genetic prion disease in Drosophila melanogaster. Neurobiol Dis 2014; 67:71-8. [PMID: 24686303 DOI: 10.1016/j.nbd.2014.03.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Revised: 02/18/2014] [Accepted: 03/20/2014] [Indexed: 11/19/2022] Open
Abstract
Prion diseases are progressive disorders that affect the central nervous system leading to memory loss, personality changes, ataxia and neurodegeneration. In humans, these disorders include Creutzfeldt-Jakob disease, kuru and Gerstmann-Straüssler-Scheinker (GSS) syndrome, the latter being a dominantly inherited prion disease associated with missense mutations in the gene that codes for the prion protein. The exact mechanism by which mutant prion proteins affect the central nervous system and cause neurological disease is not well understood. We have generated an inducible model of GSS disease in Drosophila melanogaster by temporally expressing a misfolded form of the murine prion protein in cholinergic neurons. Flies accumulating this mutant protein develop motor abnormalities which are associated with electrophysiological defects in cholinergic neurons. We find that, upon blocking the expression of the mutant protein, both behavioral and electrophysiological defects can be reversed. This represents the first case of reversibility reported in a model of genetic prion disease. Additionally, we observe that endogenous mechanisms exist within Drosophila that are capable of clearing the accumulated prion protein.
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Affiliation(s)
- A Murali
- Department of Biological Sciences, Dartmouth College, Hanover, NH 03755, USA
| | - R A Maue
- Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - P J Dolph
- Department of Biological Sciences, Dartmouth College, Hanover, NH 03755, USA.
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20
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Saverioni D, Notari S, Capellari S, Poggiolini I, Giese A, Kretzschmar HA, Parchi P. Analyses of protease resistance and aggregation state of abnormal prion protein across the spectrum of human prions. J Biol Chem 2013; 288:27972-85. [PMID: 23897825 DOI: 10.1074/jbc.m113.477547] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Prion diseases are characterized by tissue accumulation of a misfolded, β-sheet-enriched isoform (scrapie prion protein (PrP(Sc))) of the cellular prion protein (PrP(C)). At variance with PrP(C), PrP(Sc) shows a partial resistance to protease digestion and forms highly aggregated and detergent-insoluble polymers, two properties that have been consistently used to distinguish the two proteins. In recent years, however, the idea that PrP(Sc) itself comprises heterogeneous species has grown. Most importantly, a putative proteinase K (PK)-sensitive form of PrP(Sc) (sPrP(Sc)) is being increasingly investigated for its possible role in prion infectivity, neurotoxicity, and strain variability. The study of sPrP(Sc), however, remains technically challenging because of the need of separating it from PrP(C) without using proteases. In this study, we have systematically analyzed both PK resistance and the aggregation state of purified PrP(Sc) across the whole spectrum of the currently characterized human prion strains. The results show that PrP(Sc) isolates manifest significant strain-specific differences in their PK digestion profile that are only partially explained by differences in the size of aggregates, suggesting that other factors, likely acting on PrP(Sc) aggregate stability, determine its resistance to proteolysis. Fully protease-sensitive low molecular weight aggregates were detected in all isolates but in a limited proportion of the overall PrP(Sc) (i.e. <10%), arguing against a significant role of slowly sedimenting PK-sensitive PrP(Sc) in the biogenesis of prion strains. Finally, we highlight the limitations of current operational definitions of sPrP(Sc) and of the quantitative analytical measurements that are not based on the isolation of a fully PK-sensitive PrP(Sc) form.
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Affiliation(s)
- Daniela Saverioni
- From the Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy
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21
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Kraus A, Groveman BR, Caughey B. Prions and the potential transmissibility of protein misfolding diseases. Annu Rev Microbiol 2013; 67:543-64. [PMID: 23808331 DOI: 10.1146/annurev-micro-092412-155735] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Prions, or infectious proteins, represent a major frontier in the study of infectious agents. The prions responsible for mammalian transmissible spongiform encephalopathies (TSEs) are due primarily to infectious self-propagation of misfolded prion proteins. TSE prion structures remain ill-defined, other than being highly structured, self-propagating, and often fibrillar protein multimers with the capacity to seed, or template, the conversion of their normal monomeric precursors into a pathogenic form. Purified TSE prions usually take the form of amyloid fibrils, which are self-seeding ultrastructures common to many serious protein misfolding diseases such as Alzheimer's, Parkinson's, Huntington's and Lou Gehrig's (amytrophic lateral sclerosis). Indeed, recent reports have now provided evidence of prion-like propagation of several misfolded proteins from cell to cell, if not from tissue to tissue or individual to individual. These findings raise concerns that various protein misfolding diseases might have spreading, prion-like etiologies that contribute to pathogenesis or prevalence.
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Affiliation(s)
- Allison Kraus
- Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840;
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22
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Popova SN, Tarvainen I, Capellari S, Parchi P, Hannikainen P, Pirinen E, Haapasalo H, Alafuzoff I. Divergent clinical and neuropathological phenotype in a Gerstmann-Sträussler-Scheinker P102L family. Acta Neurol Scand 2012; 126:315-23. [PMID: 22211828 DOI: 10.1111/j.1600-0404.2011.01628.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/18/2011] [Indexed: 12/01/2022]
Abstract
OBJECTIVES Gerstmann-Sträussler-Scheinker syndrome belongs to the genetic prion diseases being associated with mutations in the prion protein gene (PRNP). The most common is the point mutation at codon 102, leading to the substitution of proline to leucine (P102L). Previous reports have indicated a phenotypic heterogeneity among individuals with this mutation. Here, we describe the clinical and pathological phenotype in members of the first Finnish kindred with the P102L mutation in the PNRP gene. MATERIALS AND METHODS Genetic and clinical information was available in five members of a family, while a systematic histologic and immunohistochemical assessment of the post-mortem brain was carried out in three. RESULTS Clinical presentation, disease duration and the clinical phenotype (ataxia vs dementia) varied between patients. There was a significant correlation between clinical symptoms and the neuroanatomical distribution of prion protein-immunoreactive aggregates, i.e. subtentorial predominance in ataxia vs cortical predominance in dementia. A significant concomitant Alzheimer is disease-related pathology was observed in the brain of one patient with dementia as onset symptom. CONCLUSIONS This is the first Scandinavian family carrying the P102L mutation in the PRNP gene. Gerstmann-Sträussler-Scheinker syndrome should be considered in the differential diagnosis when handling with patients with ataxia and/or dementia of unclear aetiology.
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Affiliation(s)
- S. N. Popova
- Department of Genetics and Pathology; Rudbeck's Laboratory; Uppsala University; Uppsala; Sweden
| | | | - S. Capellari
- Dipartimento di Scienze Neurologiche; Università di Bologna; Bologna; Italy
| | - P. Parchi
- Dipartimento di Scienze Neurologiche; Università di Bologna; Bologna; Italy
| | - P. Hannikainen
- Department of Forenzic Medicine; University of Eastern Finland; Kuopio; Finland
| | - E. Pirinen
- Kuopio University Hospital; Kuopio; Finland
| | - H. Haapasalo
- Department of Pathology; Centre for Laboratory Medicine; Tampere University Hospital; Tampere; Finland
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23
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Parchi P, de Boni L, Saverioni D, Cohen ML, Ferrer I, Gambetti P, Gelpi E, Giaccone G, Hauw JJ, Höftberger R, Ironside JW, Jansen C, Kovacs GG, Rozemuller A, Seilhean D, Tagliavini F, Giese A, Kretzschmar HA. Consensus classification of human prion disease histotypes allows reliable identification of molecular subtypes: an inter-rater study among surveillance centres in Europe and USA. Acta Neuropathol 2012; 124:517-29. [PMID: 22744790 DOI: 10.1007/s00401-012-1002-8] [Citation(s) in RCA: 165] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Revised: 05/30/2012] [Accepted: 06/02/2012] [Indexed: 12/27/2022]
Abstract
The current classification of human sporadic prion diseases recognizes six major phenotypic subtypes with distinctive clinicopathological features, which largely correlate at the molecular level with the genotype at the polymorphic codon 129 (methionine, M, or valine, V) in the prion protein gene and with the size of the protease-resistant core of the abnormal prion protein, PrP(Sc) (i.e. type 1 migrating at 21 kDa and type 2 at 19 kDa). We previously demonstrated that PrP(Sc) typing by Western blotting is a reliable means of strain typing and disease classification. Limitations of this approach, however, particularly in the interlaboratory setting, are the association of PrP(Sc) types 1 or 2 with more than one clinicopathological phenotype, which precludes definitive case classification if not supported by further analysis, and the difficulty of fully recognizing cases with mixed phenotypic features. In this study, we tested the inter-rater reliability of disease classification based only on histopathological criteria. Slides from 21 cases covering the whole phenotypic spectrum of human sporadic prion diseases, and also including two cases of variant Creutzfeldt-Jakob disease (CJD), were distributed blindly to 13 assessors for classification according to given instructions. The results showed good-to-excellent agreement between assessors in the classification of cases. In particular, there was full agreement (100 %) for the two most common sporadic CJD subtypes and variant CJD, and very high concordance in general for all pure phenotypes and the most common subtype with mixed phenotypic features. The present data fully support the basis for the current classification of sporadic human prion diseases and indicate that, besides molecular PrP(Sc) typing, histopathological analysis permits reliable disease classification with high interlaboratory accuracy.
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Jansen C, Parchi P, Capellari S, Ibrahim-Verbaas CA, Schuur M, Strammiello R, Corrado P, Bishop MT, van Gool WA, Verbeek MM, Baas F, van Saane W, Spliet WGM, Jansen GH, van Duijn CM, Rozemuller AJM. Human prion diseases in the Netherlands (1998-2009): clinical, genetic and molecular aspects. PLoS One 2012; 7:e36333. [PMID: 22558438 PMCID: PMC3340342 DOI: 10.1371/journal.pone.0036333] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Accepted: 04/01/2012] [Indexed: 12/30/2022] Open
Abstract
Prion diseases are rare and fatal neurodegenerative disorders that can be sporadic, inherited or acquired by infection. Based on a national surveillance program in the Netherlands we describe here the clinical, neuropathological, genetic and molecular characteristics of 162 patients with neuropathologically confirmed prion disease over a 12-year period (1998–2009). Since 1998, there has been a relatively stable mortality of Creutzfeldt-Jakob disease (CJD) in the Netherlands, ranging from 0.63 to 1.53 per million inhabitants per annum. Genetic analysis of the codon 129 methionine/valine (M/V) polymorphism in all patients with sporadic CJD (sCJD) showed a trend for under-representation of VV cases (7.0%), compared with sCJD cohorts in other Western countries, whereas the MV genotype was relatively over-represented (22,4%). Combined PrPSc and histopathological typing identified all sCJD subtypes known to date, except for the VV1 subtype. In particular, a “pure" phenotype was demonstrated in 60.1% of patients, whereas a mixed phenotype was detected in 39.9% of all sCJD cases. The relative excess of MV cases was largely accounted for by a relatively high incidence of the MV 2K subtype. Genetic analysis of the prion protein gene (PRNP) was performed in 161 patients and showed a mutation in 9 of them (5.6%), including one FFI and four GSS cases. Iatrogenic CJD was a rare phenomenon (3.1%), mainly associated with dura mater grafts. Three patients were diagnosed with new variant CJD (1.9%) and one with variably protease-sensitive prionopathy (VPSPr). Post-mortem examination revealed an alternative diagnosis in 156 patients, most commonly Alzheimer's disease (21.2%) or vascular causes of dementia (19.9%). The mortality rates of sCJD in the Netherlands are similar to those in other European countries, whereas iatrogenic and genetic cases are relatively rare. The unusual incidence of the VV2 sCJD subtype compared to that reported to date in other Western countries deserves further investigation.
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Affiliation(s)
- Casper Jansen
- Dutch Surveillance Centre for Prion Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands.
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Guan J, Mishra S, Falk RH, Liao R. Current perspectives on cardiac amyloidosis. Am J Physiol Heart Circ Physiol 2011; 302:H544-52. [PMID: 22058156 DOI: 10.1152/ajpheart.00815.2011] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Amyloidosis represents a group of diseases in which proteins undergo misfolding to form insoluble fibrils with subsequent tissue deposition. While almost all deposited amyloid fibers share a common nonbranched morphology, the affected end organs, clinical presentation, treatment strategies, and prognosis vary greatly among this group of diseases and are largely dependent on the specific amyloid precursor protein. To date, at least 27 precursor proteins have been identified to result in either local tissue or systemic amyloidosis, with nine of them manifesting in cardiac deposition and resulting in a syndrome termed "cardiac amyloidosis" or "amyloid cardiomyopathy." Although cardiac amyloidosis has been traditionally considered to be a rare disorder, as clinical appreciation and understanding continues to grow, so too has the prevalence, suggesting that this disease may be greatly underdiagnosed. The most common form of cardiac amyloidosis is associated with circulating amyloidogenic monoclonal immunoglobulin light chain proteins. Other major cardiac amyloidoses result from a misfolding of products of mutated or wild-type transthyretin protein. While the various cardiac amyloidoses share a common functional consequence, namely, an infiltrative cardiomyopathy with restrictive pathophysiology leading to progressive heart failure, the underlying pathophysiology and clinical syndrome varies with each precursor protein. Herein, we aim to provide an up-to-date overview of cardiac amyloidosis from nomenclature to molecular mechanisms and treatment options, with a particular focus on amyloidogenic immunoglobulin light chain protein cardiac amyloidosis.
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Affiliation(s)
- Jian Guan
- Cardiac Muscle Research Lab., 77 Ave. Louis Pasteur, NRB 431, Boston, MA 02115, USA
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Helmus JJ, Surewicz K, Apostol MI, Surewicz WK, Jaroniec CP. Intermolecular alignment in Y145Stop human prion protein amyloid fibrils probed by solid-state NMR spectroscopy. J Am Chem Soc 2011; 133:13934-7. [PMID: 21827207 DOI: 10.1021/ja206469q] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The Y145Stop mutant of human prion protein, huPrP23-144, has been linked to PrP cerebral amyloid angiopathy, an inherited amyloid disease, and also serves as a valuable in vitro model for investigating the molecular basis of amyloid strains. Prior studies of huPrP23-144 amyloid by magic-angle-spinning (MAS) solid-state NMR spectroscopy revealed a compact β-rich amyloid core region near the C-terminus and an unstructured N-terminal domain. Here, with the focus on understanding the higher-order architecture of huPrP23-144 fibrils, we probed the intermolecular alignment of β-strands within the amyloid core using MAS NMR techniques and fibrils formed from equimolar mixtures of (15)N-labeled protein and (13)C-huPrP23-144 prepared with [1,3-(13)C(2)] or [2-(13)C]glycerol. Numerous intermolecular correlations involving backbone atoms observed in 2D (15)N-(13)C spectra unequivocally suggest an overall parallel in-register alignment of the β-sheet core. Additional experiments that report on intermolecular (15)N-(13)CO and (15)N-(13)Cα dipolar couplings yielded an estimated strand spacing that is within ∼10% of the distances of 4.7-4.8 Å typical for parallel β-sheets.
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Affiliation(s)
- Jonathan J Helmus
- Department of Chemistry, The Ohio State University, Columbus, 43210, United States
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A Second Case of Gerstmann-Sträussler-Scheinker Disease Linked to the G131V Mutation in the Prion Protein Gene in a Dutch Patient. J Neuropathol Exp Neurol 2011; 70:698-702. [DOI: 10.1097/nen.0b013e3182270c54] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
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Abstract
The spinocerebellar ataxias (SCA) are a large group of inherited disorders affecting the cerebellum and its afferent and efferent pathways. Their hallmark symptom is slowly progressive, symmetrical, midline, and appendicular ataxia. Some may also have associated hyperkinetic movements (chorea, dystonia, myoclonus, postural/action tremor, restless legs, rubral tremor, tics), which may aid in differential diagnosis and provide treatable targets to improve performance and quality of life in these progressive, incurable conditions. The typical dominant ataxias with associated hyperkinetic movements are SCA1-3, 6-8, 12, 14, 15, 17, 19-21, and 27. The common recessive ataxias with associated hyperkinetic movements are ataxia telangiectasia and Friedreich's ataxia. Fragile X tremor-ataxia syndrome (FXTAS) and multiple-system atrophy (a sporadic ataxia which is felt to have a genetic substrate) also have hyperkinetic features. A careful work-up should be done in all apparently sporadic cases, to rule out acquired causes of ataxia, some of which can cause hyperkinetic movements in addition to ataxia. Some testing should be done even in individuals with a confirmed genetic cause, as the presence of a secondary factor (nutritional deficiency, thyroid dysfunction) can contribute to the phenotype.
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Affiliation(s)
- Susan L Perlman
- David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
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Jansen C, Voet W, Head MW, Parchi P, Yull H, Verrips A, Wesseling P, Meulstee J, Baas F, van Gool WA, Ironside JW, Rozemuller AJM. A novel seven-octapeptide repeat insertion in the prion protein gene (PRNP) in a Dutch pedigree with Gerstmann-Sträussler-Scheinker disease phenotype: comparison with similar cases from the literature. Acta Neuropathol 2011; 121:59-68. [PMID: 20198483 PMCID: PMC3015204 DOI: 10.1007/s00401-010-0656-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2009] [Revised: 02/05/2010] [Accepted: 02/13/2010] [Indexed: 11/27/2022]
Abstract
Human prion diseases can be sporadic, inherited or acquired by infection and show considerable phenotypic heterogeneity. We describe the clinical, histopathological and pathological prion protein (PrP(Sc)) characteristics of a Dutch family with a novel 7-octapeptide repeat insertion (7-OPRI) in PRNP, the gene encoding the prion protein (PrP). Clinical features were available in four, neuropathological features in three and biochemical characteristics in two members of this family. The clinical phenotype was characterized by slowly progressive cognitive decline, personality change, lethargy, depression with anxiety and panic attacks, apraxia and a hypokinetic-rigid syndrome. Neuropathological findings consisted of numerous multi- and unicentric amyloid plaques throughout the cerebrum and cerebellum with varying degrees of spongiform degeneration. Genetic and molecular studies were performed in two male family members. One of them was homozygous for valine and the other heterozygous for methionine and valine at codon 129 of PRNP. Sequence analysis identified a novel 168 bp insertion [R2-R2-R2-R2-R3g-R2-R2] in the octapeptide repeat region of PRNP. Both patients carried the mutation on the allele with valine at codon 129. Western blot analysis showed type 1 PrP(Sc) in both patients and detected a smaller ~8 kDa PrP(Sc) fragment in the cerebellum in one patient. The features of this Dutch kindred define an unusual neuropathological phenotype and a novel PRNP haplotype among the previously documented 7-OPRI mutations, further expanding the spectrum of genotype-phenotype correlations in inherited prion diseases.
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Affiliation(s)
- Casper Jansen
- Dutch Surveillance Centre for Prion Diseases, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
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Abstract
The prion diseases are a family of rare neurodegenerative disorders that result from the accumulation of a misfolded isoform of the prion protein (PrP), a normal constituent of the neuronal membrane. Five subtypes constitute the known human prion diseases; kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal insomnia (FI), and variant CJD (vCJD). These subtypes are distinguished, in part, by their clinical phenotype, but primarily by their associated brain histopathology. Evidence suggests these phenotypes are defined by differences in the pathogenic conformation of misfolded PrP. Although the vast majority of cases are sporadic, 10% to 15% result from an autosomal dominant mutation of the PrP gene (PRNP). General phenotype-genotype correlations can be made for the major subtypes of CJD, GSS, and FI. This paper will review some of the general background related to prion biology and detail the clinical and pathologic features of the major prion diseases, with a particular focus on the genetic aspects that result in prion disease or modification of its risk or phenotype.
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Affiliation(s)
- Khalilah Brown
- Center for Comprehensive Care and Research on Memory Disorders, Department of Neurology, University of Chicago, Chicago, IL 60637, USA
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31
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Ferrer I. Cognitive impairment of vascular origin: neuropathology of cognitive impairment of vascular origin. J Neurol Sci 2010; 299:139-49. [PMID: 20846674 DOI: 10.1016/j.jns.2010.08.039] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2010] [Revised: 08/15/2010] [Accepted: 08/24/2010] [Indexed: 12/31/2022]
Abstract
The term cognitive impairment of vascular origin is used to designate global cognitive deficits as well as focal neurological deficits such as aphasia, apraxia and agnosia of vascular/circulatory origin. It has been useful for identifying early clinical and neuroradiological alterations that might permit therapeutic strategies geared to curbing the progression of cerebrovascular disease. Multi-infarct encephalopathy, infarcts in strategic areas, lacunae and lacunar status, Binswanger's encephalopathy, hippocampal sclerosis, cortical granular atrophy and watershed infarcts are common lesions. Hypertension and vascular diseases such as arteriosclerosis, small blood vessel disease, inflammatory diseases of the blood vessels, Sneddon syndrome, cerebral amyloid angiopathies, cerebral autosomic dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and Maeda's syndrome are causative of cognitive impairment of vascular origin. Other less common causes are hereditary endotheliopathy with retinopathy, neuropathy and strokes (HERNS), cerebro-retinian vasculopathy (CRV), hereditary vascular retinopathy (HVR) (all three linked to 3p21.1-p21.3), hereditary infantile hemiparesis with arteriolar retinopathy and leukoencephalopathy (HIHRATL) (not linked to 3p21), fibromuscular dysplasia, and moya-moya disease. Lack of uniformity of clinical manifestations, the variety of vascular diseases and circulatory factors, the diverse, but often convergent, neuropathological substrates, and the common association with unrelated neurodegenerative diseases in the elderly, make it hard to assume a single clinical approach in the diagnosis and treatment of cognitive impairment of vascular origin. Rather, environmental and genetic risk factors, underlying vascular diseases, associated systemic, metabolic and neurodegenerative diseases and identification of extent and distribution of lesions with morphological and functional neuroimaging methods should be applied in every individual patient.
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Affiliation(s)
- Isidre Ferrer
- Institut de Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, 08907 Hospitalet de LLobregat, Spain.
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Choi JK, Jeon YC, Lee DW, Oh JM, Lee HP, Jeong BH, Carp RI, Koh YH, Kim YS. A Drosophila model of GSS syndrome suggests defects in active zones are responsible for pathogenesis of GSS syndrome. Hum Mol Genet 2010; 19:4474-89. [PMID: 20829230 DOI: 10.1093/hmg/ddq379] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
We have established a Drosophila model of Gerstmann-Sträussler-Scheinker (GSS) syndrome by expressing mouse prion protein (PrP) having leucine substitution at residue 101 (MoPrP(P101L)). Flies expressing MoPrP(P101L), but not wild-type MoPrP (MoPrP(3F4)), showed severe defects in climbing ability and early death. Expressed MoPrP(P101L) in Drosophila was differentially glycosylated, localized at the synaptic terminals and mainly present as deposits in adult brains. We found that behavioral defects and early death of MoPrP(P101L) flies were not due to Caspase 3-dependent programmed cell death signaling. In addition, we found that Type 1 glutamatergic synaptic boutons in larval neuromuscular junctions of MoPrP(P101L) flies showed significantly increased numbers of satellite synaptic boutons. Furthermore, the amount of Bruchpilot and Discs large in MoPrP(P101L) flies was significantly reduced. Brains from scrapie-infected mice showed significantly decreased ELKS, an active zone matrix marker compared with those of age-matched control mice. Thus, altered active zone structures at the molecular level may be involved in the pathogenesis of GSS syndrome in Drosophila and scrapie-infected mice.
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Affiliation(s)
- Jin-Kyu Choi
- Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyangdong Dongangu, Anyang, Gyeonggi-Do, Republic of Korea
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Parchi P, Cescatti M, Notari S, Schulz-Schaeffer WJ, Capellari S, Giese A, Zou WQ, Kretzschmar H, Ghetti B, Brown P. Agent strain variation in human prion disease: insights from a molecular and pathological review of the National Institutes of Health series of experimentally transmitted disease. Brain 2010; 133:3030-42. [PMID: 20823086 DOI: 10.1093/brain/awq234] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Six clinico-pathological phenotypes of sporadic Creutzfeldt-Jakob disease have been characterized which correlate at the molecular level with the type (1 or 2) of the abnormal prion protein, PrP(TSE), present in the brain and with the genotype of polymorphic (methionine or valine) codon 129 of the prion protein gene. However, to what extent these phenotypes with their corresponding molecular combinations (i.e. MM1, MM2, VV1 etc.) encipher distinct prion strains upon transmission remains uncertain. We studied the PrP(TSE) type and the prion protein gene in archival brain tissues from the National Institutes of Health series of transmitted Creutzfeldt-Jakob disease and kuru cases, and characterized the molecular and pathological phenotype in the affected non-human primates, including squirrel, spider, capuchin and African green monkeys. We found that the transmission properties of prions from the common sporadic Creutzfeldt-Jakob disease MM1 phenotype are homogeneous and significantly differ from those of sporadic Creutzfeldt-Jakob disease VV2 or MV2 prions. Animals injected with iatrogenic Creutzfeldt-Jakob disease MM1 and genetic Creutzfeldt-Jakob disease MM1 linked to the E200K mutation showed the same phenotypic features as those infected with sporadic Creutzfeldt-Jakob disease MM1 prions, whereas kuru most closely resembled the sporadic Creutzfeldt-Jakob disease VV2 or MV2 prion signature and neuropathology. The findings indicate that two distinct prion strains are linked to the three most common Creutzfeldt-Jakob disease clinico-pathological and molecular subtypes and kuru, and suggest that kuru may have originated from cannibalistic transmission of a sporadic Creutzfeldt-Jakob disease of the VV2 or MV2 subtype.
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Affiliation(s)
- Piero Parchi
- Department of Neurological Sciences, University of Bologna, Via Foscolo 7, Bologna, Italy.
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Protein coding of neurodegenerative dementias: the neuropathological basis of biomarker diagnostics. Acta Neuropathol 2010; 119:389-408. [PMID: 20198481 DOI: 10.1007/s00401-010-0658-1] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2009] [Revised: 02/12/2010] [Accepted: 02/13/2010] [Indexed: 12/11/2022]
Abstract
Neuropathological diagnosis of neurodegenerative dementias evolved by adapting the results of neuroanatomy, biochemistry, and cellular and molecular biology. Milestone findings of intra- and extracellular argyrophilic structures, visualizing protein deposition, initiated a protein-based classification. Widespread application of immunohistochemical and biochemical investigations revealed that (1) there are modifications of proteins intrinsic to disease (species that are phosphorylated, nitrated, oligomers, proteinase-resistant, with or without amyloid characteristics; cleavage products), (2) disease forms characterized by the accumulation of a single protein only are rather the exception than the rule, and (3) some modifications of proteins elude present neuropathological diagnostic procedures. In this review, we summarize how neuropathology, together with biochemistry, contributes to disease typing, by demonstrating a spectrum of disorders characterized by the deposition of various modifications of various proteins in various locations. Neuropathology may help to elucidate how brain pathologies alter the detectability of proteins in body fluids by upregulation of physiological forms or entrapment of different proteins. Modifications of at least the five most relevant proteins (amyloid-beta, prion protein, tau, alpha-synuclein, and TDP-43), aided by analysis of further "attracted" proteins, are pivotal to be evaluated simultaneously with different methods. This should complement the detection of biomarkers associated with pathogenetic processes, and also neuroimaging and genetic analysis, in order to obtain a highly personalized diagnostic profile. Defining clusters of patients based on the patterns of protein deposition and immunohistochemically or biochemically detectable modifications of proteins ("codes") may have higher prognostic predictive value, may be useful for monitoring therapy, and may open new avenues for research on pathogenesis.
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Jansen C, Parchi P, Capellari S, Vermeij AJ, Corrado P, Baas F, Strammiello R, van Gool WA, van Swieten JC, Rozemuller AJM. Prion protein amyloidosis with divergent phenotype associated with two novel nonsense mutations in PRNP. Acta Neuropathol 2010; 119:189-97. [PMID: 19911184 PMCID: PMC2808512 DOI: 10.1007/s00401-009-0609-x] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2009] [Revised: 10/31/2009] [Accepted: 10/31/2009] [Indexed: 12/11/2022]
Abstract
Stop codon mutations in the gene encoding the prion protein (PRNP) are very rare and have thus far only been described in two patients with prion protein cerebral amyloid angiopathy (PrP-CAA). In this report, we describe the clinical, histopathological and pathological prion protein (PrP(Sc)) characteristics of two Dutch patients carrying novel adjacent stop codon mutations in the C-terminal part of PRNP, resulting in either case in hereditary prion protein amyloidoses, but with strikingly different clinicopathological phenotypes. The patient with the shortest disease duration (27 months) carried a Y226X mutation and showed PrP-CAA without any neurofibrillary lesions, whereas the patient with the longest disease duration (72 months) had a Q227X mutation and showed an unusual Gerstmann-Sträussler-Scheinker disease phenotype with numerous cerebral multicentric amyloid plaques and severe neurofibrillary lesions without PrP-CAA. Western blot analysis in the patient with the Q227X mutation demonstrated the presence of a 7 kDa unglycosylated PrP(Sc) fragment truncated at both the N- and C-terminal ends. Our observations expand the spectrum of clinicopathological phenotypes associated with PRNP mutations and show that a single tyrosine residue difference in the PrP C-terminus may significantly affect the site of amyloid deposition and the overall phenotypic expression of the prion disease. Furthermore, it confirms that the absence of the glycosylphosphatidylinositol anchor in PrP predisposes to amyloid plaque formation.
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Affiliation(s)
- Casper Jansen
- Dutch Surveillance Centre for Prion Diseases, University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands.
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Kepe V, Ghetti B, Farlow MR, Bresjanac M, Miller K, Huang SC, Wong KP, Murrell JR, Piccardo P, Epperson F, Repovs G, Smid LM, Petric A, Siddarth P, Liu J, Satyamurthy N, Small GW, Barrio JR. PET of brain prion protein amyloid in Gerstmann-Sträussler-Scheinker disease. Brain Pathol 2009; 20:419-30. [PMID: 19725833 DOI: 10.1111/j.1750-3639.2009.00306.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
In vivo amyloid PET imaging was carried out on six symptomatic and asymptomatic carriers of PRNP mutations associated with the Gerstmann-Sträussler-Scheinker (GSS) disease, a rare familial neurodegenerative brain disorder demonstrating prion amyloid neuropathology, using 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([F-18]FDDNP). 2-Deoxy-2-[F-18]fluoro-d-glucose PET ([F-18]FDG) and magnetic resonance imaging (MRI) scans were also performed in each subject. Increased [F-18]FDDNP binding was detectable in cerebellum, neocortex and subcortical areas of all symptomatic gene carriers in close association with the experienced clinical symptoms. Parallel glucose metabolism ([F-18]FDG) reduction was observed in neocortex, basal ganglia and/or thalamus, which supports the close relationship between [F-18]FDDNP binding and neuronal dysfunction. Two asymptomatic gene carriers displayed no cortical [F-18]FDDNP binding, yet progressive [F-18]FDDNP retention in caudate nucleus and thalamus was seen at 1- and 2-year follow-up in the older asymptomatic subject. In vitro FDDNP labeling experiments on brain tissue specimens from deceased GSS subjects not participating in the in vivo studies indicated that in vivo accumulation of [F-18]FDDNP in subcortical structures, neocortices and cerebellum closely related to the distribution of prion protein pathology. These results demonstrate the feasibility of detecting prion protein accumulation in living patients with [F-18]FDDNP PET, and suggest an opportunity for its application to follow disease progression and monitor therapeutic interventions.
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Affiliation(s)
- Vladimir Kepe
- David Geffen School of Medicine at UCLA, Los Angeles, Calif 90095-6948, USA
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Jeibmann A, Paulus W. Drosophila melanogaster as a model organism of brain diseases. Int J Mol Sci 2009; 10:407-440. [PMID: 19333415 PMCID: PMC2660653 DOI: 10.3390/ijms10020407] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2008] [Revised: 01/16/2009] [Accepted: 01/20/2009] [Indexed: 01/29/2023] Open
Abstract
Drosophila melanogaster has been utilized to model human brain diseases. In most of these invertebrate transgenic models, some aspects of human disease are reproduced. Although investigation of rodent models has been of significant impact, invertebrate models offer a wide variety of experimental tools that can potentially address some of the outstanding questions underlying neurological disease. This review considers what has been gleaned from invertebrate models of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, metabolic diseases such as Leigh disease, Niemann-Pick disease and ceroid lipofuscinoses, tumor syndromes such as neurofibromatosis and tuberous sclerosis, epilepsy as well as CNS injury. It is to be expected that genetic tools in Drosophila will reveal new pathways and interactions, which hopefully will result in molecular based therapy approaches.
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Affiliation(s)
- Astrid Jeibmann
- Author to whom correspondence should be addressed; E-Mail:
; Tel. +49-251 83 57549; Fax: +49-251 83 56971
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Tunnell E, Wollman R, Mallik S, Cortes CJ, Dearmond SJ, Mastrianni JA. A novel PRNP-P105S mutation associated with atypical prion disease and a rare PrPSc conformation. Neurology 2008; 71:1431-8. [PMID: 18955686 DOI: 10.1212/01.wnl.0000330237.94742.fa] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE To define the clinicopathologic, genetic, and pathogenic prion protein (PrP(Sc)) characteristics associated with a novel mutation of the prion protein gene (PRNP). METHODS The coding segment of PRNP from the proband and family members was sequenced and the brain of the proband was histologically studied. The Western blot profile of the proteinase K (PK) resistant fraction of PrP(Sc), an approximation of its conformation, or "PrP(Sc)-type," was determined. RESULTS We detected a novel mutation at codon 105 of PRNP that results in a serine (S) substitution of proline (P) (P105S), in a young woman who developed progressive aphasia, behavioral changes, dementia, and parkinsonism, lasting 10 years to her death. Histopathologic findings included an intense focus of multicentric PrP-plaques within the hippocampus, punctate plaques scattered throughout the cerebellum, and intense spongiform degeneration focally within the putamen, suggesting a variant of Gerstmann-Sträussler-Scheinker syndrome (GSS). However, PrP(Sc)-typing revealed two PK-resistant PrP(Sc) fragments (approximately 21 and 26 kDa), a pattern not previously detected in GSS. CONCLUSIONS This mutation is the third sequence variation at codon 105 of PRNP. The unusual phenotype and PrP(Sc)-type distinguishes this genetic prion disease from typical Gerstmann-Sträussler-Scheinker syndrome and other codon 105 substitutions, suggesting that, in addition to the loss of proline at this position, the PrP(Sc) conformation and phenotype is dependent on the specific amino acid substitution.
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Affiliation(s)
- E Tunnell
- Department of Neurology, University of Chicago, Pritzker School of Medicine, 5841 So. Maryland Ave., Chicago, IL 60637, USA
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Atypical frontotemporal dementia as a new clinical phenotype of Gerstmann-Straussler-Scheinker disease with the PrP-P102L mutation. Description of a previously unreported Italian family. Neurol Sci 2008; 29:405-10. [DOI: 10.1007/s10072-008-1025-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2008] [Accepted: 08/18/2008] [Indexed: 12/11/2022]
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Cagnoli C, Brussino A, Sbaiz L, Di Gregorio E, Atzori C, Caroppo P, Orsi L, Migone N, Buffa C, Imperiale D, Brusco A. A previously undiagnosed case of Gerstmann-Sträussler-Scheinker disease revealed by PRNP gene analysis in patients with adult-onset ataxia. Mov Disord 2008; 23:1468-71. [PMID: 18566986 DOI: 10.1002/mds.21953] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Ataxia is a frequently reported symptom in prion diseases (PD) and it is characteristic of Gerstmann-Sträussler-Scheinker syndrome (GSS), a genetic PD mainly related to the P102L mutation in the PRNP gene. Our aim was to screen for the P102L and other six known PRNP gene mutations (P105L, A117V, Y145X, E200K, D202N, and V210I) a group of 206 consecutive patients diagnosed with adult-onset cerebellar ataxia of unknown origin. The patients, negative for the most common acquired and genetic forms, were analyzed using a combination of restriction endonuclease digestion and pyrosequencing; eight, affected by ataxia and cognitive dysfunction, were also sequenced for the PRNP gene. One patient resulted to be heterozygous for the P102L mutation. Retrospectively, the clinical picture was consistent with a "classical" GSS phenotype. In conclusion, the screening for the P102L mutation, or even the sequencing of the PRNP gene should be taken in consideration in patients with late-onset ataxia (>50 years).
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Affiliation(s)
- Claudia Cagnoli
- Department of Genetics, Biology and Biochemistry, University of Torino, Medical Genetics Unit, Az. Osp. San Giovanni Battista, Torino, Italy
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Uppington KM, Brown DR. Resistance of cell lines to prion toxicity aided by phospho-ERK expression. J Neurochem 2008; 105:842-52. [DOI: 10.1111/j.1471-4159.2007.05192.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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Ironside JW, Head MW. Biology and neuropathology of prion diseases. HANDBOOK OF CLINICAL NEUROLOGY 2008; 89:779-97. [PMID: 18631794 DOI: 10.1016/s0072-9752(07)01268-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- James W Ironside
- National Creutzfeldt-Jakob Disease Surveillance Unit, Western General Hospital and School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh, UK.
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Gavin BA, Dolph MJ, Deleault NR, Geoghegan JC, Khurana V, Feany MB, Dolph PJ, Supattapone S. Accelerated accumulation of misfolded prion protein and spongiform degeneration in a Drosophila model of Gerstmann-Sträussler-Scheinker syndrome. J Neurosci 2006; 26:12408-14. [PMID: 17135402 PMCID: PMC6674896 DOI: 10.1523/jneurosci.3372-06.2006] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Prion diseases are CNS disorders that can occur in sporadic, infectious, and inherited forms. Although all forms of prion disease are associated with the accumulation of pathogenic conformers of the prion protein, collectively termed PrP(Sc), the mechanisms by which PrP(Sc) molecules form and cause neuronal degeneration are unknown. Using the bipartite galactosidase-4-upstream activating sequence expression system, we generated transgenic Drosophila melanogaster heterologously expressing either wild-type (WT) or mutant, disease-associated (P101L) mouse PrP molecules in cholinergic neurons. Transgenic flies expressing neuronal P101L PrP molecules exhibited severe locomotor dysfunction and premature death as larvae and adults. These striking clinical abnormalities were accompanied by age-dependent accumulation of misfolded PrP molecules, intracellular PrP aggregates, and neuronal vacuoles. In contrast, transgenic flies expressing comparable levels of WT PrP displayed no clinical, pathological, or biochemical abnormalities. These results indicate that transgenic Drosophila expressing neuronal P101L PrP specifically exhibit several hallmark features of human Gerstmann-Sträussler-Scheinker (GSS) syndrome. Because the rates of abnormal PrP accumulation and clinical progression are highly accelerated in Drosophila compared with the rates of these processes in rodents or humans, the P101L mutant may be used for future genetic and pharmacologic studies as a novel invertebrate model of GSS.
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Affiliation(s)
- Brendan A. Gavin
- Department of Biology, Dartmouth College, Hanover, New Hampshire 03755
| | - Maria J. Dolph
- Department of Biology, Dartmouth College, Hanover, New Hampshire 03755
| | - Nathan R. Deleault
- Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, and
| | - James C. Geoghegan
- Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, and
| | - Vikram Khurana
- Department of Pathology, Division of Neuropathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
| | - Mel B. Feany
- Department of Pathology, Division of Neuropathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
| | - Patrick J. Dolph
- Department of Biology, Dartmouth College, Hanover, New Hampshire 03755
| | - Surachai Supattapone
- Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, and
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Abstract
Scintigraphic imaging of radioiodinated serum amyloid P-component is a proven method for the clinical detection of peripheral amyloid deposits (Hawkins et al., 1990). However, the inability to perform comparably high-resolution studies in experimental animal models of amyloid disease has impacted not only basic studies into the pathogenesis of amyloidosis but also in the preclinical in vivo evaluation of potential anti-amyloid therapeutic agents. We have developed microimaging technologies, implemented novel computational methods, and established protocols to generate high-resolution images of amyloid deposits in mice. (125)I-labeled serum amyloid P component (SAP) and an amyloid-fibril reactive murine monoclonal antibody (designated 11-1F4) have been used successfully to acquire high-resolution single photon emission computed tomographic (SPECT) images that, when fused with x-ray computed tomographic (CT) data, have provided precise anatomical localization of secondary (AA) and primary (AL) amyloid deposits in mouse models of these diseases. This chapter will provide detailed protocols for the radioiodination and purification of amyloidophilic proteins and the generation of mouse models of AA and AL amyloidosis. A brief description of the available hardware and the parameters used to acquire high-resolution microSPECT and CT images is presented, and the tools used to perform image reconstruction and visualization that permit the analysis and presentation of image data are discussed. Finally, we provide established methods for measuring organ- and tissue-specific activities with which to corroborate the microSPECT and CT images.
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Affiliation(s)
- Jonathan S. Wall
- Human Immunology & Cancer Program, Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN, USA ; Tel: (865) 544 9165; Fax: (865) 544 6865 ; Tel: (865) 544 9165; Fax: (865) 544 6865
| | - Michael J. Paulus
- Siemens Medical Solutions Molecular Imaging, LLC, 810 Innovation Drive, Knoxville, TN, USA ; Tel: (865) 218 1621 ; Tel: (865) 218 1642
| | - Shaun Gleason
- Siemens Medical Solutions Molecular Imaging, LLC, 810 Innovation Drive, Knoxville, TN, USA ; Tel: (865) 218 1621 ; Tel: (865) 218 1642
| | - Jens Gregor
- Department of Computer Science, University of Tennessee, 1122 Volunteer Blvd., Suite 203, Knoxville, TN 37996-3450 ; Tel: (865) 974 4399; Fax (865) 974 4404
| | - Alan Solomon
- Human Immunology & Cancer Program, Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN, USA ; Tel: (865) 544 9165; Fax: (865) 544 6865 ; Tel: (865) 544 9165; Fax: (865) 544 6865
| | - Stephen J. Kennel
- Oak Ridge National Laboratory, Life Sciences Division, Bldg 4500S, Rm F150, Oak Ridge, TN ; Tel: (865) 574 0825; Fax: (865) 576-7651
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Abstract
Human prion diseases are rare neurodegenerative disorders that can occur as sporadic, familial or acquired disorders. Within each of these categories there is a wide range of phenotypic variation that is not encountered in other neurodegenerative disorders. The identification of the prion protein and its key role in the pathogenesis of this diverse group of diseases has allowed a fuller understanding of factors that influence disease phenotype. In particular, the naturally occurring polymorphism at codon 129 in the prion protein gene has a major influence on the disease phenotype in sporadic, familial and acquired prion diseases, although the underlying mechanisms remain unclear. Recent technical advances have improved our ability to study the isoforms of the abnormal prion protein in the brain and in other tissues. This has lead to the concept of molecular strain typing, in which different isoforms of the prion protein are proposed to correspond to individual strains of the transmissible agent, each with specific biological properties. In sporadic Creutzfeldt-Jakob disease there are at least six major combinations of codon 129 genotype and prion protein isotype, which appear to relate to distinctive clinical subgroups of this disease. However, these relationships are proving to be more complex than first considered, particularly in cases with more than a single prion protein isotype in the brain. Further work is required to clarify these relationships and to explain the mechanism of neuropathological targeting of specific brain regions, which accounts for the diversity of clinical features within human prion diseases.
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Affiliation(s)
- J W Ironside
- National Creutzfeldt-Jakob Disease Surveillance Unit, Division of Pathology, University of Edinburgh, UK.
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Petersen RB, Siedlak SL, Lee HG, Kim YS, Nunomura A, Tagliavini F, Ghetti B, Cras P, Moreira PI, Castellani RJ, Guentchev M, Budka H, Ironside JW, Gambetti P, Smith MA, Perry G. Redox metals and oxidative abnormalities in human prion diseases. Acta Neuropathol 2005; 110:232-8. [PMID: 16096758 DOI: 10.1007/s00401-005-1034-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2005] [Revised: 04/18/2005] [Accepted: 04/18/2005] [Indexed: 11/30/2022]
Abstract
Prion diseases are characterized by the accumulation of diffuse and aggregated plaques of protease-resistant prion protein (PrP) in the brains of affected individuals and animals. Whereas prion diseases in animals appear to be almost exclusively transmitted by infection, human prion diseases most often occur sporadically and, to a lesser extent, by inheritance or infection. In the sporadic cases (sporadic Creutzfeld-Jakob disease, sCJD), PrP-containing plaques are infrequent, whereas in transmitted (variant CJD) and inherited (Gerstmann-Straussler-Scheinker Syndrome) cases, plaques are a usual feature. In the current study, representative cases from each of the classes of human prion disease were analyzed for the presence of markers of oxidative damage that have been found in other neurodegenerative diseases. Interestingly, we found that the pattern of deposition of PrP, amyloid-beta, and redox active metals was distinct for the various prion diseases. Whereas 8-hydroxyguanosine has been shown to be increased in sCJD, and inducible NOS is increased in scrapie-infected mice, well-studied markers of oxidative damage that accumulate in the lesions of other neurodegenerative diseases (such as Alzheimer's disease, progressive supranuclear palsy, and Parkinson's disease), such as heme oxygenase-1 and lipid peroxidation, were not found around PrP deposits or in vulnerable neurons. These findings suggest an important distinction in prion-related oxidative stress, indicating that different neurodegenerative pathways are involved in different prion diseases.
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Affiliation(s)
- Robert B Petersen
- Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA
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