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1
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Xu Q, Liu D, Zhu L, Su Y, Huang H. Long non-coding RNAs as key regulators of neurodegenerative protein aggregation. Alzheimers Dement 2025; 21:e14498. [PMID: 39936251 PMCID: PMC11815248 DOI: 10.1002/alz.14498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 11/26/2024] [Accepted: 12/02/2024] [Indexed: 02/13/2025]
Abstract
The characteristic events in neurodegenerative diseases (NDDs) encompass protein misfolding, aggregation, accumulation, and their related cellular dysfunction, synaptic function loss. While distinct proteins are implicated in the pathological processes of different NDDs, the process of protein misfolding and aggregation remains notably similar across various conditions. Specifically, proteins undergo misfolding into beta-folded (β-folded) conformation, resulting in the formation of insoluble amyloid proteins. Despite advancements in comprehending protein aggregation, certain facets of this intricate process remain incompletely elucidated. In recent years, the concept that long non-coding RNAs (lncRNAs) contribute to protein aggregation has gained recognition. LncRNAs influence the formation of protein aggregates by facilitating protein overexpression through the regulation of gene transcription and translation, inhibiting protein degradation via lysosomal and autophagic pathways, and targeting aberrant modifications and phase transitions of proteins. A better understanding of the relationship between lncRNAs and aberrant protein aggregation is an important step in dissecting the underlying molecular mechanisms and will contribute to the discovery of new therapeutic targets and strategies. HIGHLIGHTS: NDDs are marked by protein misfolding, aggregation, and accumulation, leading to cellular dysfunction and loss of synaptic function. Despite different proteins being involved in various NDDs, the process of misfolding into β-folded conformations and forming insoluble amyloid proteins is consistent across conditions. The role of lncRNAs in protein aggregation has gained attention, as they regulate gene transcription and translation, inhibit protein degradation, and target aberrant protein modifications. Understanding the link between lncRNAs and protein aggregation is crucial for uncovering molecular mechanisms and developing new therapeutic targets.
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Affiliation(s)
- Qi Xu
- Department of NeurologyUnion HospitalHuazhong University of Science and TechnologyWuhanChina
| | - Dan Liu
- Department of GeneticsSchool of Basic MedicineTongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiChina
| | - Ling‐Qiang Zhu
- Department of PathophysiologySchool of Basic MedicineTongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiChina
| | - Ying Su
- Department of NeurologyUnion HospitalHuazhong University of Science and TechnologyWuhanChina
| | - He‐Zhou Huang
- Department of PathophysiologySchool of Basic MedicineTongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiChina
- Department of Anesthesiology DepartmentUnion Hospital, Huazhong University of Science and TechnologyWuhanChina
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Fröhlich A, Pfaff AL, Middlehurst B, Hughes LS, Bubb VJ, Quinn JP, Koks S. Deciphering the role of a SINE-VNTR-Alu retrotransposon polymorphism as a biomarker of Parkinson's disease progression. Sci Rep 2024; 14:10932. [PMID: 38740892 DOI: 10.1038/s41598-024-61753-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 05/09/2024] [Indexed: 05/16/2024] Open
Abstract
SINE-VNTR-Alu (SVA) retrotransposons are transposable elements which represent a source of genetic variation. We previously demonstrated that the presence/absence of a human-specific SVA, termed SVA_67, correlated with the progression of Parkinson's disease (PD). In the present study, we demonstrate that SVA_67 acts as expression quantitative trait loci, thereby exhibiting a strong regulatory effect across the genome using whole genome and transcriptomic data from the Parkinson's progression markers initiative cohort. We further show that SVA_67 is polymorphic for its variable number tandem repeat domain which correlates with both regulatory properties in a luciferase reporter gene assay in vitro and differential expression of multiple genes in vivo. Additionally, this variation's utility as a biomarker is reflected in a correlation with a number of PD progression markers. These experiments highlight the plethora of transcriptomic and phenotypic changes associated with SVA_67 polymorphism which should be considered when investigating the missing heritability of neurodegenerative diseases.
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Affiliation(s)
- Alexander Fröhlich
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
- Perron Institute for Neurological and Translational Science, Perth, WA, Australia
| | - Abigail L Pfaff
- Perron Institute for Neurological and Translational Science, Perth, WA, Australia
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia
| | - Ben Middlehurst
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Lauren S Hughes
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Vivien J Bubb
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - John P Quinn
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
| | - Sulev Koks
- Perron Institute for Neurological and Translational Science, Perth, WA, Australia.
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia.
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3
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Lane-Donovan C, Boxer AL. Disentangling tau: One protein, many therapeutic approaches. Neurotherapeutics 2024; 21:e00321. [PMID: 38278659 PMCID: PMC10963923 DOI: 10.1016/j.neurot.2024.e00321] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 01/09/2024] [Accepted: 01/09/2024] [Indexed: 01/28/2024] Open
Abstract
The tauopathies encompass over 20 adult neurodegenerative diseases and are characterized by the dysfunction and accumulation of insoluble tau protein. Among them, Alzheimer's disease, frontotemporal dementia, and progressive supranuclear palsy collectively impact millions of patients and their families worldwide. Despite years of drug development using a variety of mechanisms of action, no therapeutic directed against tau has been approved for clinical use. This raises important questions about our current model of tau pathology and invites thoughtful consideration of our approach to nonclinical models and clinical trial design. In this article, we review what is known about the biology and genetics of tau, placing it in the context of current and failed clinical trials. We highlight potential reasons for the lack of success to date and offer suggestions for new pathways in therapeutic development. Overall, our viewpoint to the future is optimistic for this important group of neurodegenerative diseases.
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Affiliation(s)
- Courtney Lane-Donovan
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA 94158, USA.
| | - Adam L Boxer
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA 94158, USA
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4
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Cherian A, K P D, Vijayaraghavan A. Parkinson's disease - genetic cause. Curr Opin Neurol 2023; Publish Ahead of Print:00019052-990000000-00070. [PMID: 37366140 DOI: 10.1097/wco.0000000000001167] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/28/2023]
Abstract
PURPOSE OF REVIEW Our knowledge of the genetic architecture underlying Parkinson's disease has vastly improved in the past quarter century. About 5-10% of all patients suffer from a monogenic form of Parkinson's disease. RECENT FINDINGS Mutations in autosomal dominant genes (e.g. SNCA, LRRK2, VPS35) or autosomal recessive genes (e.g. PRKN, PINK1, DJ-1) can cause genetic Parkinson's disease. Recessive DNAJC6 mutations can present predominantly as atypical parkinsonism, but also rarely as typical Parkinson's disease. Majority of Parkinson's disease is genetically complex. Mutation in RIC3, a chaperone of neuronal nicotinic acetylcholine receptor subunit α-7 (CHRNA7), provides strong evidence for the role of cholinergic pathway, for the first time, in cause of Parkinson's disease. X-linked parkinsonism manifests at a young age accompanied by many (atypical) features such as intellectual disability, spasticity, seizures, myoclonus, dystonia, and have poor response to levodopa. SUMMARY This review article aims to provide a comprehensive overview on Parkinson's disease genetics. MAPT, which encodes the microtubule associated protein tau, TMEM230, LRP10, NUS1 and ARSA are the five new putative disease-causing genes in Parkinson's disease. The validation of novel genes and its association with Parkinson's disease remains extremely challenging, as genetically affected families are sparse and globally widespread. In the near future, genetic discoveries in Parkinson's disease will influence our ability to predict and prognosticate the disease, help in defining etiological subtypes that are critical in implementation of precision medicine.
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Affiliation(s)
- Ajith Cherian
- Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India
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5
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Yuan A, Nixon RA. Posttranscriptional regulation of neurofilament proteins and tau in health and disease. Brain Res Bull 2023; 192:115-127. [PMID: 36441047 PMCID: PMC9907725 DOI: 10.1016/j.brainresbull.2022.10.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 10/20/2022] [Accepted: 10/26/2022] [Indexed: 01/16/2023]
Abstract
Neurofilament and tau proteins are neuron-specific cytoskeletal proteins that are enriched in axons, regulated by many of the same protein kinases, interact physically, and are the principal constituents of neurofibrillary lesions in major adult-onset dementias. Both proteins share functions related to the modulation of stability and functions of the microtubule network in axons, axonal transport and scaffolding of organelles, long-term synaptic potentiation, and learning and memory. Expression of these proteins is regulated not only at the transcriptional level but also through posttranscriptional control of pre-mRNA splicing, mRNA stability, transport, localization, local translation and degradation. Current evidence suggests that posttranscriptional determinants of their levels are usually regulated by RNA-binding proteins and microRNAs primarily through 3'-untranslated regions of neurofilament and tau mRNAs. Dysregulations of neurofilament and tau expression caused by mutations or pathologies of RNA-binding proteins such as TDP43, FUS and microRNAs are increasingly recognized in association with varied neurological disorders. In this review, we summarize the current understanding of posttranscriptional control of neurofilament and tau by examining the posttranscriptional regulation of neurofilament and tau by RNA-binding proteins and microRNAs implicated in health and diseases.
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Affiliation(s)
- Aidong Yuan
- Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA; Department of Psychiatry, New York University Langone Health, New York, NY 10016, USA; NYU Neuroscience Institute, New York University Langone Health, New York, NY 10016, USA.
| | - Ralph A. Nixon
- Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA,Department of Psychiatry, New York University Langone Health, New York, NY 10016, USA,Department of Cell Biology, New York University Langone Health, New York, NY 10016, USA,NYU Neuroscience Institute, New York University Langone Health, New York, NY 10016, USA,Correspondence to: Center for Dementia Research, Nathan Kline Institute, New York University Langone Health, New York, NY 10016, USA, (A. Yuan), (R.A. Nixon)
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6
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Torres-Garcia L, P Domingues JM, Brandi E, Haikal C, Mudannayake JM, Brás IC, Gerhardt E, Li W, Svanbergsson A, Outeiro TF, Gouras GK, Li JY. Monitoring the interactions between alpha-synuclein and Tau in vitro and in vivo using bimolecular fluorescence complementation. Sci Rep 2022; 12:2987. [PMID: 35194057 PMCID: PMC8863885 DOI: 10.1038/s41598-022-06846-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 01/31/2022] [Indexed: 12/12/2022] Open
Abstract
Parkinson's disease (PD) and Alzheimer's disease (AD) are characterized by pathological accumulation and aggregation of different amyloidogenic proteins, α-synuclein (aSyn) in PD, and amyloid-β (Aβ) and Tau in AD. Strikingly, few PD and AD patients' brains exhibit pure pathology with most cases presenting mixed types of protein deposits in the brain. Bimolecular fluorescence complementation (BiFC) is a technique based on the complementation of two halves of a fluorescent protein, which allows direct visualization of protein-protein interactions. In the present study, we assessed the ability of aSyn and Tau to interact with each other. For in vitro evaluation, HEK293 and human neuroblastoma cells were used, while in vivo studies were performed by AAV6 injection in the substantia nigra pars compacta (SNpc) of mice and rats. We observed that the co-expression of aSyn and Tau led to the emergence of fluorescence, reflecting the interaction of the proteins in cell lines, as well as in mouse and rat SNpc. Thus, our data indicates that aSyn and Tau are able to interact with each other in a biologically relevant context, and that the BiFC assay is an effective tool for studying aSyn-Tau interactions in vitro and in different rodent models in vivo.
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Affiliation(s)
- Laura Torres-Garcia
- Experimental Dementia Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
- Neural Plasticity and Repair Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Joana M P Domingues
- Neural Plasticity and Repair Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
- Department of Clinical Neurosciences, University of Cambridge, The Clifford Albbutt Building, Cambridge, UK
| | - Edoardo Brandi
- Neural Plasticity and Repair Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Caroline Haikal
- Neural Plasticity and Repair Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Janitha M Mudannayake
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, and Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Inês C Brás
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Germany
| | - Ellen Gerhardt
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Germany
| | - Wen Li
- Neural Plasticity and Repair Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
- Institute of Health Sciences, China Medical University, Shenyang, China
| | - Alexander Svanbergsson
- Neural Plasticity and Repair Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Tiago F Outeiro
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Germany
- Max Planck Institute for Experimental Medicine, Göttingen, Germany
- Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
- Scientific Employee With an Honorary Contract at German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Gunnar K Gouras
- Experimental Dementia Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.
| | - Jia-Yi Li
- Neural Plasticity and Repair Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.
- Institute of Health Sciences, China Medical University, Shenyang, China.
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7
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Wu F, Wang DD, Shi HH, Wang CC, Xue CH, Wang YM, Zhang TT. N-3 PUFA-Deficiency in Early Life Exhibits Aggravated MPTP-Induced Neurotoxicity in Old Age while Supplementation with DHA/EPA-Enriched Phospholipids Exerts a Neuroprotective Effect. Mol Nutr Food Res 2021; 65:e2100339. [PMID: 34378848 DOI: 10.1002/mnfr.202100339] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 08/04/2021] [Indexed: 11/10/2022]
Abstract
INTRODUCTION Malnutrition in early life affects the growth and development of fetus and children, which has a long-term impact on adult health. Previous studies reveal a relationship between dietary omega-3 polyunsaturated fatty acid (n-3 PUFA) content, brain development, and the prevalence of neurodevelopmental disorders and inflammation. However, it is unclear about the effect of n-3 PUFA-deficiency in early life on the development of Parkinson's disease (PD) in old age, as well as the neuroprotective effect of DHA- and EPA-enriched phospholipids (DHA/EPA-PLs) supplemented in old age in long-term n-3 PUFA-deficient mice. METHODS AND RESULTS The PD mice induced by 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) in n-3 PUFA-adequate (N) and -deficient (DEF) group are supplemented with a DHA/EPA-PLs diet for 2 weeks (N+DPL, DEF+DPL). DHA/EPA-PLs supplementation significantly protects against MPTP-induced impairments. The DEF+DPL group shows poorer motor performance, the loss of dopaminergic neurons, mitochondrial dysfunction, and neurodevelopment delay than the N+DPL group, and still did not recover to the Control level. CONCLUSIONS Dietary n-3 PUFA-deficiency in early life exhibits more aggravated MPTP-induced neurotoxicity in old age, than DHA/EPA-PLs supplementation recovers brain DHA levels and exerts neuroprotective effects in old age in long-term n-3 PUFA-deficient mice, which might provide a potential dietary guidance.
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Affiliation(s)
- Fang Wu
- College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong, 266003, China
| | - Dan-Dan Wang
- College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong, 266003, China
| | - Hao-Hao Shi
- College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong, 266003, China
| | - Cheng-Cheng Wang
- College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong, 266003, China
| | - Chang-Hu Xue
- College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong, 266003, China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, Shandong Province, 266237, China
| | - Yu-Ming Wang
- College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong, 266003, China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, Shandong Province, 266237, China
| | - Tian-Tian Zhang
- College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong, 266003, China
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8
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Root J, Merino P, Nuckols A, Johnson M, Kukar T. Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis. Neurobiol Dis 2021; 154:105360. [PMID: 33812000 PMCID: PMC8113138 DOI: 10.1016/j.nbd.2021.105360] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 03/16/2021] [Accepted: 03/29/2021] [Indexed: 12/11/2022] Open
Abstract
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative disorders that are thought to exist on a clinical and pathological spectrum. FTD and ALS are linked by shared genetic causes (e.g. C9orf72 hexanucleotide repeat expansions) and neuropathology, such as inclusions of ubiquitinated, misfolded proteins (e.g. TAR DNA-binding protein 43; TDP-43) in the CNS. Furthermore, some genes that cause FTD or ALS when mutated encode proteins that localize to the lysosome or modulate endosome-lysosome function, including lysosomal fusion, cargo trafficking, lysosomal acidification, autophagy, or TFEB activity. In this review, we summarize evidence that lysosomal dysfunction, caused by genetic mutations (e.g. C9orf72, GRN, MAPT, TMEM106B) or toxic-gain of function (e.g. aggregation of TDP-43 or tau), is an important pathogenic disease mechanism in FTD and ALS. Further studies into the normal function of many of these proteins are required and will help uncover the mechanisms that cause lysosomal dysfunction in FTD and ALS. Mutations or polymorphisms in genes that encode proteins important for endosome-lysosome function also occur in other age-dependent neurodegenerative diseases, including Alzheimer's (e.g. APOE, PSEN1, APP) and Parkinson's (e.g. GBA, LRRK2, ATP13A2) disease. A more complete understanding of the common and unique features of lysosome dysfunction across the spectrum of neurodegeneration will help guide the development of therapies for these devastating diseases.
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Affiliation(s)
- Jessica Root
- Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta 30322, Georgia; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta 30322, Georgia
| | - Paola Merino
- Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta 30322, Georgia; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta 30322, Georgia
| | - Austin Nuckols
- Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta 30322, Georgia; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta 30322, Georgia
| | - Michelle Johnson
- Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta 30322, Georgia; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta 30322, Georgia
| | - Thomas Kukar
- Department of Pharmacology and Chemical Biology, Emory University, School of Medicine, Atlanta 30322, Georgia; Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta 30322, Georgia; Department of Neurology, Emory University, School of Medicine, Atlanta 30322, Georgia.
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9
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Cherian A, Divya KP. Genetics of Parkinson's disease. Acta Neurol Belg 2020; 120:1297-1305. [PMID: 32813147 DOI: 10.1007/s13760-020-01473-5] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 08/11/2020] [Indexed: 12/21/2022]
Abstract
Less than a quarter century after the discovery of SNCA as the first attributable gene in Parkinson's disease (PD), our knowledge of the genetic architecture underlying this disease has improved by leaps and bounds. About 5-10% of all patients suffer from a monogenic form of PD where mutations in autosomal-dominant (AD) genes-SNCA, LRRK2, and VPS35 and autosomal recessive (AR) genes-PINK1, DJ-1, and Parkin cause the disease. Whole-exome sequencing has described AR DNAJC6 mutations not only in predominantly atypical, but also in patients with typical PD. Majority of PD is genetically complex, caused by the combination of common genetic variants in concert with environmental factors. Genome-wide association studies have identified twenty six PD risk loci till date; however, these show only moderate effects on the risk for PD. The validation of novel genes and its association with PD remains extremely challenging as families harboring rare genetic variants are sparse and globally widespread. This review article aims to provide a comprehensive overview on PD genetics.
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Affiliation(s)
- Ajith Cherian
- Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India, 695011
| | - K P Divya
- Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India, 695011.
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10
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Lill CM. WITHDRAWN: Genetics of Parkinson's disease. Mol Cell Probes 2020:101471. [PMID: 31978549 DOI: 10.1016/j.mcp.2019.101471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 10/17/2019] [Indexed: 11/25/2022]
Abstract
The Publisher regrets that this article is an accidental duplication of an article that has already been published, DOI of original article: https://doi.org/10.1016/j.mcp.2016.11.001. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
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Affiliation(s)
- Christina M Lill
- Genetic and Molecular Epidemiology Group, Institute of Neurogenetics, University of Lübeck, Maria-Goeppert-Str. 1, 23562, Lübeck, Germany
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11
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Sánchez-Juan P, Moreno S, de Rojas I, Hernández I, Valero S, Alegret M, Montrreal L, García González P, Lage C, López-García S, Rodrííguez-Rodríguez E, Orellana A, Tárraga L, Boada M, Ruiz A. The MAPT H1 Haplotype Is a Risk Factor for Alzheimer's Disease in APOE ε4 Non-carriers. Front Aging Neurosci 2019; 11:327. [PMID: 31866851 PMCID: PMC6905227 DOI: 10.3389/fnagi.2019.00327] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 11/12/2019] [Indexed: 01/12/2023] Open
Abstract
An ancestral inversion of 900 kb on chromosome 17q21, which includes the microtubule-associated protein tau (MAPT) gene, defines two haplotype clades in Caucasians (H1 and H2). The H1 haplotype has been linked inconsistently with AD. In a previous study, we showed that an SNP tagging this haplotype (rs1800547) was associated with AD risk in a large population from the Dementia Genetics Spanish Consortium (DEGESCO) including 4435 cases and 6147 controls. The association was mainly driven by individuals that were non-carriers of the APOE ε4 allele. Our aim was to replicate our previous findings in an independent sample of 4124 AD cases and 3290 controls from Spain (GR@ACE project) and to analyze the effect of the H1 sub-haplotype structure on the risk of AD. The H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0025). Stratification analysis showed that this association was mainly driven by the APOE ε4 non-carriers (OR = 1.15; p = 0.0022). Pooled analysis of both Spanish datasets (n = 17,996) showed that the highest AD risk related to the MAPT H1/H2 haplotype was in those individuals that were the oldest [third tertile (>77 years)] and did not carry APOE ε4 allele (p = 0.001). We did not find a significant association between H1 sub-haplotypes and AD. H1c was nominally associated but lost statistical significance after adjusting by population sub-structure. Our results are consistent with the hypothesis that genetic variants linked to the MAPT H1/H2 are tracking a genuine risk allele for AD. The fact that this association is stronger in APOE ε4 non-carriers partially explains previous controversial results and might be related to a slower alternative causal pathway less dependent on brain amyloid load.
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Affiliation(s)
- Pascual Sánchez-Juan
- Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain.,Service of Neurology, University Hospital Marqués de Valdecilla, IDIVAL, University of Cantabria, Santander, Spain
| | - Sonia Moreno
- Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain.,Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
| | - Itziar de Rojas
- Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain.,Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
| | - Isabel Hernández
- Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain.,Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
| | - Sergi Valero
- Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain.,Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
| | - Montse Alegret
- Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain.,Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
| | - Laura Montrreal
- Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain
| | - Pablo García González
- Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain.,Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
| | - Carmen Lage
- Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain.,Service of Neurology, University Hospital Marqués de Valdecilla, IDIVAL, University of Cantabria, Santander, Spain
| | - Sara López-García
- Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain.,Service of Neurology, University Hospital Marqués de Valdecilla, IDIVAL, University of Cantabria, Santander, Spain
| | - Eloy Rodrííguez-Rodríguez
- Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain.,Service of Neurology, University Hospital Marqués de Valdecilla, IDIVAL, University of Cantabria, Santander, Spain
| | - Adelina Orellana
- Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain
| | - Lluís Tárraga
- Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain.,Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
| | - Mercè Boada
- Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain.,Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
| | - Agustín Ruiz
- Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain.,Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
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12
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Tan MMX, Malek N, Lawton MA, Hubbard L, Pittman AM, Joseph T, Hehir J, Swallow DMA, Grosset KA, Marrinan SL, Bajaj N, Barker RA, Burn DJ, Bresner C, Foltynie T, Hardy J, Wood N, Ben-Shlomo Y, Grosset DG, Williams NM, Morris HR. Genetic analysis of Mendelian mutations in a large UK population-based Parkinson's disease study. Brain 2019; 142:2828-2844. [PMID: 31324919 PMCID: PMC6735928 DOI: 10.1093/brain/awz191] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 04/05/2019] [Accepted: 04/28/2019] [Indexed: 01/01/2023] Open
Abstract
Our objective was to define the prevalence and clinical features of genetic Parkinson's disease in a large UK population-based cohort, the largest multicentre prospective clinico-genetic incident study in the world. We collected demographic data, Movement Disorder Society Unified Parkinson's Disease Rating Scale scores, and Montreal Cognitive Assessment scores. We analysed mutations in PRKN (parkin), PINK1, LRRK2 and SNCA in relation to age at symptom onset, family history and clinical features. Of the 2262 participants recruited to the Tracking Parkinson's study, 424 had young-onset Parkinson's disease (age at onset ≤ 50) and 1799 had late onset Parkinson's disease. A range of methods were used to genotype 2005 patients: 302 young-onset patients were fully genotyped with multiplex ligation-dependent probe amplification and either Sanger and/or exome sequencing; and 1701 late-onset patients were genotyped with the LRRK2 'Kompetitive' allele-specific polymerase chain reaction assay and/or exome sequencing (two patients had missing age at onset). We identified 29 (1.4%) patients carrying pathogenic mutations. Eighteen patients carried the G2019S or R1441C mutations in LRRK2, and one patient carried a heterozygous duplication in SNCA. In PRKN, we identified patients carrying deletions of exons 1, 4 and 5, and P113Xfs, R275W, G430D and R33X. In PINK1, two patients carried deletions in exon 1 and 5, and the W90Xfs point mutation. Eighteen per cent of patients with age at onset ≤30 and 7.4% of patients from large dominant families carried pathogenic Mendelian gene mutations. Of all young-onset patients, 10 (3.3%) carried biallelic mutations in PRKN or PINK1. Across the whole cohort, 18 patients (0.9%) carried pathogenic LRRK2 mutations and one (0.05%) carried an SNCA duplication. There is a significant burden of LRRK2 G2019S in patients with both apparently sporadic and familial disease. In young-onset patients, dominant and recessive mutations were equally common. There were no differences in clinical features between LRRK2 carriers and non-carriers. However, we did find that PRKN and PINK1 mutation carriers have distinctive clinical features compared to young-onset non-carriers, with more postural symptoms at diagnosis and less cognitive impairment, after adjusting for age and disease duration. This supports the idea that there is a distinct clinical profile of PRKN and PINK1-related Parkinson's disease. We estimate that there are approaching 1000 patients with a known genetic aetiology in the UK Parkinson's disease population. A small but significant number of patients carry causal variants in LRRK2, SNCA, PRKN and PINK1 that could potentially be targeted by new therapies, such as LRRK2 inhibitors.
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Affiliation(s)
- Manuela M X Tan
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
- UCL Movement Disorders Centre, University College London, London, UK
| | - Naveed Malek
- Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK
| | | | - Leon Hubbard
- Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
| | - Alan M Pittman
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
| | - Theresita Joseph
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
| | - Jason Hehir
- University College London Hospitals NHS Foundation Trust, UK
| | - Diane M A Swallow
- Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK
| | - Katherine A Grosset
- Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK
| | - Sarah L Marrinan
- Institute of Neuroscience, University of Newcastle, Newcastle upon Tyne, UK
| | - Nin Bajaj
- Department of Clinical Neurosciences, University of Nottingham, UK
| | - Roger A Barker
- UCL Movement Disorders Centre, University College London, London, UK
- Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge UK
- Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, Cambridge, UK
| | - David J Burn
- Institute of Neuroscience, University of Newcastle, Newcastle upon Tyne, UK
| | - Catherine Bresner
- Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
| | - Thomas Foltynie
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
- UCL Movement Disorders Centre, University College London, London, UK
| | - John Hardy
- Reta Lila Weston Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
| | - Nicholas Wood
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
- UCL Movement Disorders Centre, University College London, London, UK
| | | | - Donald G Grosset
- Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK
| | - Nigel M Williams
- Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
| | - Huw R Morris
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
- UCL Movement Disorders Centre, University College London, London, UK
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13
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Xia L, Xia K, Weinberger D, Zhang F. Common genetic variants shared among five major psychiatric disorders: a large-scale genome-wide combined analysis. ACTA ACUST UNITED AC 2019. [DOI: 10.36316/gcatr.01.0003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background. Genetic correlation and pleiotropic effects among psychiatric disorders have been reported. This study aimed to identify specific common genetic variants shared between five adult psychiatric disorders: schizophrenia, bipolar, major depressive disorder, attention deficit-hyperactivity disorder, and autism spectrum disorder.
Methods. A combined p-value of about 8 million single nucleotide polymorphisms (SNPs) was calculated in an equivalent sample of 151,672 cases and 284,444 controls of European ancestry from published data based on the latest genome-wide association studies of five major psychiatric disorder. SNPs that achieved genome-wide significance (P<5x10-08) were mapped to loci and genomic regions for further investigation; gene annotation and clustering were performed to understand the biological process and molecular function of the loci identified. We also examined CNVs and performed expression quantitative trait loci analysis for SNPs by genomic region.
Results. We find that 6,293 SNPs mapped to 336 loci shared by the three adult psychiatric disorders, 1,108 variants at 73 loci shared by the childhood disorders, and 713 variants at 47 genes shared by all five disorders at genome-wide significance (P<5x10-08). Of the 2,583 SNPs at the extended major histocompatibility complex identified for three adult disorders, none of them were associated with childhood disorders; and SNPs shared by all five disorders were located in regions that have been identified as containing copy number variation associated with autism and had largely neurodevelopmental functions.
Conclusion. We show a number of specific SNPs associated with psychiatric disorders of childhood or adult-onset, illustrating not only genetic heterogeneity across these disorders but also developmental genes shared by them all. These results provide a manageable list of anchors from which to investigate epigenetic mechanism or gene-gene interaction on the development of neuropsychiatric disorders and for developing a measurement matrix for disease risk to potentially develop a novel taxonomy for precision medicine.
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Affiliation(s)
- Lu Xia
- Global Clinical and Translational Research Institute
| | - Kun Xia
- The Central South University
| | | | - Fengyu Zhang
- Global Clinical and Translational Research Institute
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14
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Drosophila Models of Sporadic Parkinson's Disease. Int J Mol Sci 2018; 19:ijms19113343. [PMID: 30373150 PMCID: PMC6275057 DOI: 10.3390/ijms19113343] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 10/22/2018] [Accepted: 10/23/2018] [Indexed: 12/17/2022] Open
Abstract
Parkinson’s disease (PD) is the most common cause of movement disorders and is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. It is increasingly recognized as a complex group of disorders presenting widely heterogeneous symptoms and pathology. With the exception of the rare monogenic forms, the majority of PD cases result from an interaction between multiple genetic and environmental risk factors. The search for these risk factors and the development of preclinical animal models are in progress, aiming to provide mechanistic insights into the pathogenesis of PD. This review summarizes the studies that capitalize on modeling sporadic (i.e., nonfamilial) PD using Drosophilamelanogaster and discusses their methodologies, new findings, and future perspectives.
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15
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Pihlstrøm L, Wiethoff S, Houlden H. Genetics of neurodegenerative diseases: an overview. HANDBOOK OF CLINICAL NEUROLOGY 2018; 145:309-323. [PMID: 28987179 DOI: 10.1016/b978-0-12-802395-2.00022-5] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Genetic factors are central to the etiology of neurodegeneration, both as monogenic causes of heritable disease and as modifiers of susceptibility to complex, sporadic disorders. Over the last two decades, the identification of disease genes and risk loci has led to some of the greatest advances in medicine and invaluable insights into pathogenic mechanisms and disease pathways. Large-scale research efforts, novel study designs, and advances in methodology are rapidly expanding our understanding of the genome and the genetic architecture of neurodegenerative disease. Here, we review major developments in the field to date, highlighting overarching historic trends and general insights. Monogenic neurodegenerative diseases are discussed from the perspectives of both rare Mendelian forms of common disorders, such as Alzheimer disease and Parkinson disease, and heterogeneous heritable conditions, including ataxias and spastic paraplegias. Next, we summarize the experiences from investigations of complex neurodegenerative disorders, including genomewide association studies. In the final section, we reflect upon the limitations of current findings and outline important future directions. Genetics plays an essential role in translational research, ultimately aiming to develop novel disease-modifying therapies for neurodegenerative disorders. We anticipate that individual genetic profiling will also be increasingly relevant in a clinical context, with implications for patient care in line with the proposed ideal of personalized medicine.
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Affiliation(s)
- Lasse Pihlstrøm
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway; UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, United Kingdom
| | - Sarah Wiethoff
- UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, United Kingdom; Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, Tübingen, Germany
| | - Henry Houlden
- UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, United Kingdom.
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16
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Abstract
Since the first formal description of Parkinson disease (PD) two centuries ago, our understanding of this common neurodegenerative disorder has expanded at all levels of description, from the delineation of its clinical phenotype to the identification of its neuropathological features, neurochemical processes and genetic factors. Along the way, findings have led to novel hypotheses about how the disease develops and progresses, challenging our understanding of how neurodegenerative disorders wreak havoc on human health. In this Timeline article, I recount the fascinating 200-year journey of PD research.
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Affiliation(s)
- Serge Przedborski
- Departments of Neurology, Pathology, and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA
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17
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Huynh TPV, Davis AA, Ulrich JD, Holtzman DM. Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins. J Lipid Res 2017; 58:824-836. [PMID: 28246336 DOI: 10.1194/jlr.r075481] [Citation(s) in RCA: 157] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 02/25/2017] [Indexed: 12/13/2022] Open
Abstract
Alzheimer's disease (AD) is one of the fastest-growing causes of death and disability in persons 65 years of age or older, affecting more than 5 million Americans alone. Clinical manifestations of AD include progressive decline in memory, executive function, language, and other cognitive domains. Research efforts within the last three decades have identified APOE as the most significant genetic risk factor for late-onset AD, which accounts for >99% of cases. The apoE protein is hypothesized to affect AD pathogenesis through a variety of mechanisms, from its effects on the blood-brain barrier, the innate immune system, and synaptic function to the accumulation of amyloid-β (Aβ). Here, we discuss the role of apoE on the biophysical properties and metabolism of the Aβ peptide, the principal component of amyloid plaques and cerebral amyloid angiopathy (CAA). CAA is characterized by the deposition of amyloid proteins (including Aβ) in the leptomeningeal medium and small arteries, which is found in most AD cases but sometimes occurs as an independent entity. Accumulation of these pathologies in the brain is one of the pathological hallmarks of AD. Beyond Aβ, we will extend the discussion to the potential role of apoE on other amyloidogenic proteins found in AD, and also a number of diverse neurodegenerative diseases.
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Affiliation(s)
- Tien-Phat V Huynh
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO 63110
| | - Albert A Davis
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO 63110
| | - Jason D Ulrich
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO 63110
| | - David M Holtzman
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO 63110
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18
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Rittman T, Rubinov M, Vértes PE, Patel AX, Ginestet CE, Ghosh BCP, Barker RA, Spillantini MG, Bullmore ET, Rowe JB. Regional expression of the MAPT gene is associated with loss of hubs in brain networks and cognitive impairment in Parkinson disease and progressive supranuclear palsy. Neurobiol Aging 2016; 48:153-160. [PMID: 27697694 PMCID: PMC5096886 DOI: 10.1016/j.neurobiolaging.2016.09.001] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 08/12/2016] [Accepted: 09/02/2016] [Indexed: 01/08/2023]
Abstract
Abnormalities of tau protein are central to the pathogenesis of progressive supranuclear palsy, whereas haplotype variation of the tau gene MAPT influences the risk of Parkinson disease and Parkinson's disease dementia. We assessed whether regional MAPT expression might be associated with selective vulnerability of global brain networks to neurodegenerative pathology. Using task-free functional magnetic resonance imaging in progressive supranuclear palsy, Parkinson disease, and healthy subjects (n = 128), we examined functional brain networks and measured the connection strength between 471 gray matter regions. We obtained MAPT and SNCA microarray expression data in healthy subjects from the Allen brain atlas. Regional connectivity varied according to the normal expression of MAPT. The regional expression of MAPT correlated with the proportionate loss of regional connectivity in Parkinson's disease. Executive cognition was impaired in proportion to the loss of hub connectivity. These effects were not seen with SNCA, suggesting that alpha-synuclein pathology is not mediated through global network properties. The results establish a link between regional MAPT expression and selective vulnerability of functional brain networks to neurodegeneration.
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Affiliation(s)
- Timothy Rittman
- Department of Clinical Neurosciences, University of Cambridge, Herchel Smith Building for Brain and Mind Sciences, Cambridge, UK; Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.
| | - Mikail Rubinov
- Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK; Department of Psychiatry, Herchel Smith Building for Brain and Mind Sciences, Cambridge, UK; Churchill College, University of Cambridge, Cambridge, UK
| | - Petra E Vértes
- Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK; Department of Psychiatry, Herchel Smith Building for Brain and Mind Sciences, Cambridge, UK
| | - Ameera X Patel
- Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK; Department of Psychiatry, Herchel Smith Building for Brain and Mind Sciences, Cambridge, UK
| | - Cedric E Ginestet
- Department of Biostatistics, Institute of Psychiatry Psychology and Neuroscience, King's College London, London, UK
| | - Boyd C P Ghosh
- Wessex Neurological Centre, University Hospital Southampton, Southampton, UK
| | - Roger A Barker
- Department of Clinical Neurosciences, University of Cambridge, Herchel Smith Building for Brain and Mind Sciences, Cambridge, UK; Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK; John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK
| | - Maria Grazia Spillantini
- Department of Clinical Neurosciences, University of Cambridge, Herchel Smith Building for Brain and Mind Sciences, Cambridge, UK; John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK
| | - Edward T Bullmore
- Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK; Department of Psychiatry, Herchel Smith Building for Brain and Mind Sciences, Cambridge, UK
| | - James B Rowe
- Department of Clinical Neurosciences, University of Cambridge, Herchel Smith Building for Brain and Mind Sciences, Cambridge, UK; Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK; Medical Research Council Cognition and Brain Sciences Unit, Cambridge, UK
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19
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Lill CM. Genetics of Parkinson's disease. Mol Cell Probes 2016; 30:386-396. [PMID: 27818248 DOI: 10.1016/j.mcp.2016.11.001] [Citation(s) in RCA: 224] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Revised: 11/02/2016] [Accepted: 11/02/2016] [Indexed: 12/30/2022]
Abstract
Almost two decades after the identification of SNCA as the first causative gene in Parkinson's disease (PD) and the subsequent understanding that genetic factors play a substantial role in PD development, our knowledge of the genetic architecture underlying this disease has vastly improved. Approximately 5-10% of patients suffer from a monogenic form of PD where autosomal dominant mutations in SNCA, LRRK2, and VPS35 and autosomal recessive mutations in PINK1, DJ-1, and Parkin cause the disease with high penetrance. Furthermore, recent whole-exome sequencing have described autosomal recessive DNAJC6 mutations in predominately atypical, but also cases with typical PD. In addition, several other genes have been linked to atypical Parkinsonian phenotypes. However, the vast majority of PD is genetically complex, i.e. it is caused by the combined action of common genetic variants in concert with environmental factors. By the application of genome-wide association studies, 26 PD risk loci have been established to date. Similar to other genetically complex diseases, these show only moderate effects on PD risk. Increasing this etiologic complexity, many of the involved genetic and environmental risk factors likely interact in an intricate fashion. This article aims to provide a comprehensive overview of the current knowledge in PD genetics.
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Affiliation(s)
- Christina M Lill
- Genetic and Molecular Epidemiology Group, Institute of Neurogenetics, University of Lübeck, Maria-Goeppert-Str. 1, 23562, Lübeck, Germany.
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20
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Wong YC, Krainc D. Lysosomal trafficking defects link Parkinson's disease with Gaucher's disease. Mov Disord 2016; 31:1610-1618. [PMID: 27619775 DOI: 10.1002/mds.26802] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 08/15/2016] [Accepted: 08/17/2016] [Indexed: 01/17/2023] Open
Abstract
Lysosomal dysfunction has been implicated in multiple diseases, including lysosomal storage disorders such as Gaucher's disease, in which loss-of-function mutations in the GBA1 gene encoding the lysosomal hydrolase β-glucocerebrosidase result in lipid substrate accumulation. In Parkinson's disease, α-synuclein accumulates in Lewy bodies and neurites contributing to neuronal death. Previous clinical and genetic evidence has demonstrated an important link between Parkinson's and Gaucher's disease, as GBA1 mutations and variants increase the risk of Parkinson's and Parkinson's patients exhibit decreased β-glucocerebrosidase activity. Using human midbrain neuron cultures, we have found that loss of β-glucocerebrosidase activity promotes α-synuclein accumulation and toxicity, whereas α-synuclein accumulation further contributes to decreased lysosomal β-glucocerebrosidase activity by disrupting β-glucocerebrosidase trafficking to lysosomes. Moreover, α-synuclein accumulation disrupts trafficking of additional lysosomal hydrolases, further contributing to lysosomal dysfunction and neuronal dyshomeostasis. Importantly, promoting β-glucocerebrosidase activity reduces α-synuclein accumulation and rescues lysosomal and neuronal dysfunction, suggesting that β-glucocerebrosidase may be an important therapeutic target for advancing drug discovery in synucleinopathies including Parkinson's disease. © 2016 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Yvette C Wong
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Dimitri Krainc
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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21
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Pastor P, Moreno F, Clarimón J, Ruiz A, Combarros O, Calero M, López de Munain A, Bullido MJ, de Pancorbo MM, Carro E, Antonell A, Coto E, Ortega-Cubero S, Hernandez I, Tárraga L, Boada M, Lleó A, Dols-Icardo O, Kulisevsky J, Vázquez-Higuera JL, Infante J, Rábano A, Fernández-Blázquez MÁ, Valentí M, Indakoetxea B, Barandiarán M, Gorostidi A, Frank-García A, Sastre I, Lorenzo E, Pastor MA, Elcoroaristizabal X, Lennarz M, Maier W, Rámirez A, Serrano-Ríos M, Lee SE, Sánchez-Juan P. MAPT H1 Haplotype is Associated with Late-Onset Alzheimer's Disease Risk in APOEɛ4 Noncarriers: Results from the Dementia Genetics Spanish Consortium. J Alzheimers Dis 2016; 49:343-52. [PMID: 26444794 DOI: 10.3233/jad-150555] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ4 noncarriers (OR = 1.14; p = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p = 0.0003) and PSP (OR = 3.18; p = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ4 AD.
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Affiliation(s)
- Pau Pastor
- Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra (CIMA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Department of Neurology, Hospital Universitari Mutua de Terrassa, University of Barcelona School of Medicine, Barcelona, Spain
| | - Fermín Moreno
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Department of Neurology. Hospital Universitario Donostia. San Sebastián, Spain
| | - Jordi Clarimón
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Neurology Department, Hospital de la Santa Creu i Sant Pau - Biomedical Research Institute Sant Pau - Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Agustín Ruiz
- Memory Clinic of Fundaciò ACE, Institut Catalá de Neurociències Aplicades, Barcelona, Spain
| | - Onofre Combarros
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Neurology Service, University Hospital Marqués de Valdecilla (University of Cantabria and IDIVAL), Santander, Spain
| | - Miguel Calero
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Memory Clinic of Fundaciò ACE, Institut Catalá de Neurociències Aplicades, Barcelona, Spain
| | - Adolfo López de Munain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Department of Neurology. Hospital Universitario Donostia. San Sebastián, Spain.,Neurosciences Area, Institute Biodonostia and Department of Neurosciences, University of Basque Country, UPV-EHU San Sebastián, Spain
| | - Maria J Bullido
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.,Institute of Sanitary Research"Hospital la Paz" (IdIPaz), Madrid, Spain
| | - Marian M de Pancorbo
- BIOMICs Research Group, Centro de Investigación "Lascaray" Ikergunea, Universidad del País Vasco UPV/EHU, Vitoria-Gasteiz, Spain
| | - Eva Carro
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Neuroscience Group, Instituto de Investigacion Hospital 12 de Octubre (i+12), Madrid, Spain
| | - Anna Antonell
- Alzheimer's disease and other cognitive disorders Unit, Neurology Department, Hospital Clínic, IDIBAPS, Barcelona, Spain
| | - Eliecer Coto
- Molecular Genetics Laboratory, Genetics Unit, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Sara Ortega-Cubero
- Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra (CIMA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain
| | - Isabel Hernandez
- Memory Clinic of Fundaciò ACE, Institut Catalá de Neurociències Aplicades, Barcelona, Spain
| | - Lluís Tárraga
- Memory Clinic of Fundaciò ACE, Institut Catalá de Neurociències Aplicades, Barcelona, Spain
| | - Mercè Boada
- Memory Clinic of Fundaciò ACE, Institut Catalá de Neurociències Aplicades, Barcelona, Spain
| | - Alberto Lleó
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Neurology Department, Hospital de la Santa Creu i Sant Pau - Biomedical Research Institute Sant Pau - Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Oriol Dols-Icardo
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Neurology Department, Hospital de la Santa Creu i Sant Pau - Biomedical Research Institute Sant Pau - Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Jaime Kulisevsky
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Neurology Department, Hospital de la Santa Creu i Sant Pau - Biomedical Research Institute Sant Pau - Universitat Autònoma de Barcelona, Barcelona, Spain.,Universitat Oberta de Catalunya (UOC), Barcelona, Spain
| | - José Luis Vázquez-Higuera
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Neurology Service, University Hospital Marqués de Valdecilla (University of Cantabria and IDIVAL), Santander, Spain
| | - Jon Infante
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Neurology Service, University Hospital Marqués de Valdecilla (University of Cantabria and IDIVAL), Santander, Spain
| | - Alberto Rábano
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Department of Neuropathology and Tissue Bank, Alzheimer Disease Research Unit, CIEN Foundation, Carlos III Institute of Health, Alzheimer Center Reina Sofia Foundation, Madrid, Spain
| | - Miguel Ángel Fernández-Blázquez
- Alzheimer Disease Research Unit, CIEN Foundation, Alzheimer Center Reina Sofia Foundation, Carlos III Institute of Health, Madrid, Spain
| | - Meritxell Valentí
- Alzheimer Disease Research Unit, CIEN Foundation, Alzheimer Center Reina Sofia Foundation, Carlos III Institute of Health, Madrid, Spain
| | - Begoña Indakoetxea
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Department of Neurology. Hospital Universitario Donostia. San Sebastián, Spain
| | - Myriam Barandiarán
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Department of Neurology. Hospital Universitario Donostia. San Sebastián, Spain
| | - Ana Gorostidi
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Neurosciences Area, Institute Biodonostia and Department of Neurosciences, University of Basque Country, UPV-EHU San Sebastián, Spain
| | - Ana Frank-García
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Institute of Sanitary Research"Hospital la Paz" (IdIPaz), Madrid, Spain.,NeurologyService, Hospital Universitario La Paz (UAM), Madrid, Spain
| | - Isabel Sastre
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.,Institute of Sanitary Research"Hospital la Paz" (IdIPaz), Madrid, Spain
| | - Elena Lorenzo
- Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra (CIMA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain
| | - María A Pastor
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain.,Neuroimaging Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Xabier Elcoroaristizabal
- BIOMICs Research Group, Centro de Investigación "Lascaray" Ikergunea, Universidad del País Vasco UPV/EHU, Vitoria-Gasteiz, Spain
| | - Martina Lennarz
- Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany
| | - Wolfang Maier
- Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.,German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Alfredo Rámirez
- Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.,Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Manuel Serrano-Ríos
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) Spain, Hospital Clínico San Carlos, Madrid, Spain
| | - Suzee E Lee
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA
| | - Pascual Sánchez-Juan
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.,Neurology Service, University Hospital Marqués de Valdecilla (University of Cantabria and IDIVAL), Santander, Spain
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22
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Cervera-Carles L, Pagonabarraga J, Pascual-Sedano B, Pastor P, Campolongo A, Fortea J, Blesa R, Alcolea D, Morenas-Rodríguez E, Sala I, Lleó A, Kulisevsky J, Clarimón J. Copy number variation analysis of the 17q21.31 region and its role in neurodegenerative diseases. Am J Med Genet B Neuropsychiatr Genet 2016; 171B:175-80. [PMID: 26453547 DOI: 10.1002/ajmg.b.32390] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 10/02/2015] [Indexed: 12/31/2022]
Abstract
The H1 haplotype of the 17q21.31 inversion polymorphism has been consistently associated with progressive supranuclear palsy, corticobasal degeneration, and Parkinson's disease in Caucasians. Recently, large polymorphic segmental duplications resulting into complex rearrangements at this locus with a high diversity range in human populations have been revealed. We sought to explore whether the two multi-allelic copy number variants that are present in the H1 clade (with segmental duplications of 300 and 218 kilobases in length) could be responsible for the known H1-related risk of developing these neurodegenerative disorders. A total of 857 Spanish subjects including 330 patients with Parkinson's disease, 96 with progressive supranuclear palsy, 55 with corticobasal degeneration, 51 dementia with Lewy bodies, and 325 neurologically healthy controls, were genotyped for the H1/H2 haplotype. Subsequently, the two copy number variants that are characteristic of the H1 haplotype were evaluated through a high-resolution approach based on droplet digital polymerase chain reaction, in all H1 homozygous subjects. The H1 allele was significantly overrepresented in all diagnostic groups compared with controls (Parkinson's disease, P = 0.0001; progressive supranuclear palsy, P = 1.22 × 10(-6) ; corticobasal degeneration, P = 0.0002; and dementia with Lewy bodies, P = 0.032). However, no dosage differences were found for any of the two copy number variants analyzed. The H1 haplotype is associated with the risk of several neurodegenerative disorders, including dementia with Lewy bodies. However, common structural diversity within the 17q21.31-H1 clade does not explain this genetic association.
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Affiliation(s)
- Laura Cervera-Carles
- Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Javier Pagonabarraga
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.,Movement Disorders Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Berta Pascual-Sedano
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.,Movement Disorders Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Pau Pastor
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.,Memory and Movement Disorders Units, Department of Neurology, University Hospital Mútua de Terrassa, Barcelona, Spain
| | - Antonia Campolongo
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.,Movement Disorders Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Juan Fortea
- Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Rafael Blesa
- Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Daniel Alcolea
- Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Estrella Morenas-Rodríguez
- Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Isabel Sala
- Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Alberto Lleó
- Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Jaime Kulisevsky
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.,Movement Disorders Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Jordi Clarimón
- Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
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23
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Genetic Profile, Environmental Exposure, and Their Interaction in Parkinson's Disease. PARKINSONS DISEASE 2016; 2016:6465793. [PMID: 26942037 PMCID: PMC4752982 DOI: 10.1155/2016/6465793] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Revised: 01/05/2016] [Accepted: 01/10/2016] [Indexed: 12/15/2022]
Abstract
The discovery of causative mutations for Parkinson's disease (PD) as well as their functional characterization in cellular and animal models has provided crucial insight into the pathogenesis of this disorder. Today, we know that PD pathogenesis involves multiple related processes including mitochondrial dysfunction, oxidative and nitrative stress, microglial activation and inflammation, and aggregation of α-synuclein and impaired autophagy. However, with the exception of a few families with Mendelian inheritance, the cause of PD in most individuals is yet unknown and the identified genetic susceptibility factors have only small effect size. Epidemiologic studies have found increased risk of PD associated with exposure to environmental toxicants such as pesticides, organic solvents, metals, and air pollutants, while reduced risk of PD associated with smoking cigarettes and coffee consumption. The role of environmental exposure, as well as the contribution of single genetic risk factors, is still controversial. In most of PD cases, disease onset is probably triggered by a complex interplay of many genetic and nongenetic factors, each of which conveys a minor increase in the risk of disease. This review summarizes the current knowledge on causal mutation for PD, susceptibility factors increasing disease risk, and the genetic factors that modify the impact of environmental exposure.
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24
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Harel T, Posey JE, Graham BH, Walkiewicz M, Yang Y, Lalani SR, Belmont JW. Atypical presentation of moyamoya disease in an infant with a de novo RNF213 variant. Am J Med Genet A 2015. [PMID: 26198278 DOI: 10.1002/ajmg.a.37230] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Variants in RNF213 lead to susceptibility to moyamoya disease, a rare cerebral angiopathy characterized by bilateral stenosis of the internal carotid arteries and development of a compensatory collateral network. We describe a 3-month-old female with seizures, arterial narrowing involving the internal carotid and intracranial arteries and inferior abdominal aorta, and persistently elevated transaminases. Whole exome sequencing demonstrated a novel de novo variant in RNF213, securing a molecular diagnosis and directing appropriate intervention. This report underscores the role of whole exome sequencing in cases for which a complex and atypical presentation may mask diagnosis. Furthermore, the early and severe presentation in our patient, in conjunction with a novel de novo RNF213 variant, suggests that specific variants in RNF213 may lead to a Mendelian form of disease rather than simply conferring susceptibility to multifactorial disease.
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Affiliation(s)
- Tamar Harel
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Jennifer E Posey
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Brett H Graham
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Magdalena Walkiewicz
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Yaping Yang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Seema R Lalani
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - John W Belmont
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
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25
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Golpich M, Amini E, Hemmati F, Ibrahim NM, Rahmani B, Mohamed Z, Raymond AA, Dargahi L, Ghasemi R, Ahmadiani A. Glycogen synthase kinase-3 beta (GSK-3β) signaling: Implications for Parkinson's disease. Pharmacol Res 2015; 97:16-26. [PMID: 25829335 DOI: 10.1016/j.phrs.2015.03.010] [Citation(s) in RCA: 213] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 03/05/2015] [Accepted: 03/16/2015] [Indexed: 01/02/2023]
Abstract
Glycogen synthase kinase 3 (GSK-3) dysregulation plays an important role in the pathogenesis of numerous disorders, affecting the central nervous system (CNS) encompassing both neuroinflammation and neurodegenerative diseases. Several lines of evidence have illustrated a key role of the GSK-3 and its cellular and molecular signaling cascades in the control of neuroinflammation. Glycogen synthase kinase 3 beta (GSK-3β), one of the GSK-3 isomers, plays a major role in neuronal apoptosis and its inhibition decreases expression of alpha-Synuclein (α-Synuclein), which make this kinase an attractive therapeutic target for neurodegenerative disorders. Parkinson's disease (PD) is a chronic neurodegenerative movement disorder characterized by the progressive and massive loss of dopaminergic neurons by neuronal apoptosis in the substantia nigra pars compacta and depletion of dopamine in the striatum, which lead to pathological and clinical abnormalities. Thus, understanding the role of GSK-3β in PD will enhance our knowledge of the basic mechanisms underlying the pathogenesis of this disorder and facilitate the identification of new therapeutic avenues. In recent years, GSK-3β has been shown to play essential roles in modulating a variety of cellular functions, which have prompted efforts to develop GSK-3β inhibitors as therapeutics. In this review, we summarize GSK-3 signaling pathways and its association with neuroinflammation. Moreover, we highlight the interaction between GSK-3β and several cellular processes involved in the pathogenesis of PD, including the accumulation of α-Synuclein aggregates, oxidative stress and mitochondrial dysfunction. Finally, we discuss about GSK-3β inhibitors as a potential therapeutic strategy in PD.
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Affiliation(s)
- Mojtaba Golpich
- Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia
| | - Elham Amini
- Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia
| | - Fatemeh Hemmati
- Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia
| | - Norlinah Mohamed Ibrahim
- Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia
| | - Behrouz Rahmani
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahurin Mohamed
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Azman Ali Raymond
- Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia
| | - Leila Dargahi
- NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Rasoul Ghasemi
- Neurophysiology Research Center and Department of Physiology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Abolhassan Ahmadiani
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
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26
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Verstraeten A, Theuns J, Van Broeckhoven C. Progress in unraveling the genetic etiology of Parkinson disease in a genomic era. Trends Genet 2015; 31:140-9. [PMID: 25703649 DOI: 10.1016/j.tig.2015.01.004] [Citation(s) in RCA: 168] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2014] [Revised: 01/21/2015] [Accepted: 01/22/2015] [Indexed: 01/30/2023]
Abstract
Parkinson disease (PD) and Parkinson-plus syndromes are genetically heterogeneous neurological diseases. Initial studies into the genetic causes of PD relied on classical molecular genetic approaches in well-documented case families. More recently, these approaches have been combined with exome sequencing and together have identified 15 causal genes. Additionally, genome-wide association studies (GWASs) have discovered over 25 genetic risk factors. Elucidation of the genetic architecture of sporadic and familial parkinsonism, however, has lagged behind that of simple Mendelian conditions, suggesting the existence of features confounding genetic data interpretation. Here we discuss the successes and potential pitfalls of gene discovery in PD and related disorders in the post-genomic era. With an estimated 30% of trait variance currently unexplained, tackling current limitations will further expedite gene discovery and lead to increased application of these genetic insights in molecular diagnostics using gene panel and exome sequencing strategies.
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Affiliation(s)
- Aline Verstraeten
- Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born Bunge, University of Antwerp, Antwerp, Belgium
| | - Jessie Theuns
- Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born Bunge, University of Antwerp, Antwerp, Belgium
| | - Christine Van Broeckhoven
- Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born Bunge, University of Antwerp, Antwerp, Belgium.
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27
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Xiao J, Vemula S, Yue Z. Rodent Models of Autosomal Dominant Parkinson Disease. Mov Disord 2015. [DOI: 10.1016/b978-0-12-405195-9.00018-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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28
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Moehle MS, West AB. M1 and M2 immune activation in Parkinson's Disease: Foe and ally? Neuroscience 2014; 302:59-73. [PMID: 25463515 DOI: 10.1016/j.neuroscience.2014.11.018] [Citation(s) in RCA: 150] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Revised: 10/03/2014] [Accepted: 11/06/2014] [Indexed: 12/20/2022]
Abstract
Parkinson's Disease (PD) is a chronic and progressive neurodegenerative disorder of unknown etiology. Autopsy findings, genetics, retrospective studies, and molecular imaging all suggest a role for inflammation in the neurodegenerative process. However, relatively little is understood about the causes and implications of neuroinflammation in PD. Understanding how inflammation arises in PD, in particular the activation state of cells of the innate immune system, may provide an exciting opportunity for novel neuroprotective therapeutics. We analyze the evidence of immune system involvement in PD susceptibility, specifically in the context of M1 and M2 activation states. Tracking and modulating these activation states may provide new insights into both PD etiology and therapeutic strategies.
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Affiliation(s)
- M S Moehle
- Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL, United States.
| | - A B West
- Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL, United States
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29
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CSF levels of DJ-1 and tau distinguish MSA patients from PD patients and controls. Parkinsonism Relat Disord 2014; 20:112-5. [DOI: 10.1016/j.parkreldis.2013.09.003] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Revised: 08/30/2013] [Accepted: 09/03/2013] [Indexed: 11/21/2022]
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30
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Parkinsonism. Neurogenetics 2012. [DOI: 10.1017/cbo9781139087711.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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31
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Khandelwal PJ, Dumanis SB, Herman AM, Rebeck GW, Moussa CEH. RETRACTED: Wild type and P301L mutant Tau promote neuro-inflammation and α-Synuclein accumulation in lentiviral gene delivery models. Mol Cell Neurosci 2012; 49:44-53. [PMID: 21945393 PMCID: PMC3246111 DOI: 10.1016/j.mcn.2011.09.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2011] [Revised: 09/02/2011] [Accepted: 09/06/2011] [Indexed: 01/15/2023] Open
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. Concerns about the article were raised on PubPeer [https://pubpeer.com/publications/DA4525FDCD8F7FEA2E4ACC9EC9322F] namely that in the western blots there are similarities between Fig. 1D and 1E, Fig. 2B duplicates Fig. 3E, Fig. 4L duplicates Fig. 5A and Fig. 4A partly duplicates Fig. 4F, and Figure 2D is the same as Figure 1B in Algarzae, N., Hebron, M., Miessau, M., Moussa, C.E.H., 2012. Parkin prevents cortical atrophy and Ab-induced alterations of brain metabolism: 13C NMR and magnetic resonance imaging studies in AD models. Neuroscience 225, 22-34. The corresponding author was not able to provide the raw data, and therefore requested to retract the article. Authors Charbel E.-H. Moussa, G. William Rebeck and Alexander M. Herman agreed to this retraction, Preeti J. Khandelwal and Sonya B. Dumanis are no longer in science and could not be contacted.
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Affiliation(s)
- Preeti J Khandelwal
- Department of Neuroscience, Georgetown University Medical Center. Washington D.C. 20007 USA
| | - Sonya B Dumanis
- Department of Neuroscience, Georgetown University Medical Center. Washington D.C. 20007 USA
| | - Alexander M Herman
- Department of Biochemistry Molecular and Cell Biology, Georgetown University Medical Center, Washington D.C., 20007 USA
| | - G William Rebeck
- Department of Neuroscience, Georgetown University Medical Center. Washington D.C. 20007 USA
| | - Charbel E-H Moussa
- Department of Neuroscience, Georgetown University Medical Center. Washington D.C. 20007 USA; Department of Biochemistry Molecular and Cell Biology, Georgetown University Medical Center, Washington D.C., 20007 USA.
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32
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Chung RH, Martin ER. Single-marker family-based association analysis conditional on parental information. Methods Mol Biol 2012; 850:359-70. [PMID: 22307708 DOI: 10.1007/978-1-61779-555-8_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Family-based designs have been commonly used in association studies. Different family structures such as extended pedigrees and nuclear families, including parent-offspring triads and families with multiple affected siblings (multiplex families), can be ascertained for family-based association analysis. Flexible association tests that can accommodate different family structures have been proposed. The pedigree disequilibrium test (PDT) (Am J Hum Genet 67:146-154, 2000) can use full genotype information from general (possibly extended) pedigrees with one or multiple affected siblings but requires parental genotypes or genotypes of unaffected siblings. On the other hand, the association in the presence of linkage (APL) test (Am J Hum Genet 73:1016-1026, 2003) is restricted to nuclear families with one or more affected siblings but can infer missing parental genotypes properly by accounting for identity-by-descent (IBD) parameters. Both the PDT and APL are powerful association tests in the presence of linkage and can be used as complementary tools for association analysis. This chapter introduces these two tests and compares their properties. Recommendations and notes for performing the tests in practice are provided.
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Affiliation(s)
- Ren-Hua Chung
- John P. Hussman Institute for Human Genomics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
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33
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Abstract
We have witnessed tremendous success in genome-wide association studies (GWAS) in recent years. Since the identification of variants in the complement factor H gene on the risk of age-related macular degeneration, GWAS have become ubiquitous in genetic studies and have led to the identification of genetic variants that are associated with a variety of complex human diseases and traits. These discoveries have changed our understanding of the biological architecture of common, complex diseases and have also provided new hypotheses to test. New tools, such as next-generation sequencing, will be an important part of the future of genetics research; however, GWAS studies will continue to play an important role in disease gene discovery. Many traits have yet to be explored by GWAS, especially in minority populations, and large collaborative studies are currently being conducted to maximize the return from existing GWAS data. In addition, GWAS technology continues to improve, increasing genomic coverage for major global populations and decreasing the cost of experiments. Although much of the variance attributable to genetic factors for many important traits is still unexplained, GWAS technology has been instrumental in mapping over a thousand genes to hundreds of traits. More discoveries are made each month and the scale, quality and quantity of current work has a steady trend upward. We briefly review the current key trends in GWAS, which can be summarized with three goals: increase power, increase collaborations and increase populations.
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Morris M, Koyama A, Masliah E, Mucke L. Tau reduction does not prevent motor deficits in two mouse models of Parkinson's disease. PLoS One 2011; 6:e29257. [PMID: 22206005 PMCID: PMC3242771 DOI: 10.1371/journal.pone.0029257] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2011] [Accepted: 11/23/2011] [Indexed: 11/18/2022] Open
Abstract
Many neurodegenerative diseases are increasing in prevalence and cannot be prevented or cured. If they shared common pathogenic mechanisms, treatments targeting such mechanisms might be of benefit in multiple conditions. The tau protein has been implicated in the pathogenesis of diverse neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Tau reduction prevents cognitive deficits, behavioral abnormalities and other pathological changes in multiple AD mouse models. Here we examined whether tau reduction also prevents motor deficits and pathological alterations in two mouse models of PD, generated by unilateral striatal injection of 6-hydroxydopamine (6-OHDA) or transgene-mediated neuronal expression of human wildtype α-synuclein. Both models were evaluated on Tau(+/+), Tau(+/-) and Tau(-/-) backgrounds in a variety of motor tests. Tau reduction did not prevent motor deficits caused by 6-OHDA and slightly worsened one of them. Tau reduction also did not prevent 6-OHDA-induced loss of dopaminergic terminals in the striatum. Similarly, tau reduction did not prevent motor deficits in α-synuclein transgenic mice. Our results suggest that tau has distinct roles in the pathogeneses of AD and PD and that tau reduction may not be of benefit in the latter condition.
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Affiliation(s)
- Meaghan Morris
- Gladstone Institute of Neurological Disease, San Francisco, California, United States of America
- Biochemistry, Cellular and Molecular Biology Graduate Program, Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Akihiko Koyama
- Gladstone Institute of Neurological Disease, San Francisco, California, United States of America
| | - Eliezer Masliah
- Departments of Neuroscience and Pathology, University of California San Diego, La Jolla, California, United States of America
| | - Lennart Mucke
- Gladstone Institute of Neurological Disease, San Francisco, California, United States of America
- Department of Neurology, University of California San Francisco, San Francisco, California, United States of America
- * E-mail:
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Khandelwal PJ, Herman AM, Moussa CEH. Inflammation in the early stages of neurodegenerative pathology. J Neuroimmunol 2011; 238:1-11. [PMID: 21820744 DOI: 10.1016/j.jneuroim.2011.07.002] [Citation(s) in RCA: 153] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2011] [Revised: 07/09/2011] [Accepted: 07/12/2011] [Indexed: 12/12/2022]
Abstract
Inflammation is secondary to protein accumulation in neurodegenerative diseases, including Alzheimer's, Parkinson's and Amyotrophic Lateral Sclerosis. Emerging evidence indicate sustained inflammatory responses, involving microglia and astrocytes in animal models of neurodegeneration. It is unknown whether inflammation is beneficial or detrimental to disease progression and how inflammatory responses are induced within the CNS. Persistence of an inflammatory stimulus or failure to resolve sustained inflammation can result in pathology, thus, mechanisms that counteract inflammation are indispensable. Here we review studies on inflammation mediated by innate and adaptive immunity in the early stages of neurodegeneration and highlight important areas for future investigation.
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Affiliation(s)
- Preeti J Khandelwal
- Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20007, USA
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36
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Cummings AC, Lee SL, McCauley JL, Jiang L, Crunk A, McFarland LL, Gallins PJ, Fuzzell D, Knebusch C, Jackson CE, Scott WK, Pericak-Vance MA, Haines JL. A genome-wide linkage screen in the Amish with Parkinson disease points to chromosome 6. Ann Hum Genet 2011; 75:351-8. [PMID: 21488853 DOI: 10.1111/j.1469-1809.2011.00643.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Parkinson disease (PD) is a common complex neurodegenerative disorder with an underlying genetic etiology that has been difficult to dissect. Although some PD risk genes have been discovered, most of the underlying genetic etiology remains unknown. To further elucidate the genetic component, we have undertaken a genome-wide linkage screen in an isolated founder population of Amish living in the Midwestern United States. We performed tests for linkage and for association using a marker set of nearly 6000 single-nucleotide polymorphisms. Parametric multipoint linkage analysis generated a logarithm of the odds of linkage (LOD) score of 2.44 on chromosome 6 in the SYNE1 gene, approximately 8 Mbp from the PARK2 gene. In a different region on chromosome 6 (∼67 Mbp from PARK2) an association was found for rs4302647 (p < 4.0 × 10(-6) ), which is not within 300 kb of any gene. While the association exceeds Bonferroni correction, it may yet represent a false positive due to the small sample size and the low minor allele frequency. The minor allele frequency in affecteds is 0.07 compared to 0.01 in unaffecteds. Taken together, these results support involvement of loci on chromosome 6 in the genetic etiology of PD.
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Affiliation(s)
- Anna C Cummings
- Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA
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Wang KS, Mullersman JE, Liu XF. Family-based association analysis of the MAPT gene in Parkinson disease. J Appl Genet 2011; 51:509-14. [PMID: 21063069 DOI: 10.1007/bf03208881] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The MAPT gene has been shown to be associated with several neurodegenerative disorders, including forms of parkinsonism and Parkinson disease (PD), but the results reveal population differences. We investigated the association of 10 single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 with PD and age at onset, by using 443 discordant sib pairs in PD from a public dataset (Mayo-Perlegen LEAPS Collaboration). Association with PD was assessed by the FBAT using generalized estimating equations (FBAT-GEE), while the association with age at onset as a quantitative trait was evaluated using the FBAT-logrank statistic. Five SNPs were significantly associated with PD (P < 0.05) in an additive model, and 9 SNPs were associated with PD (P < 0.05) in dominant and recessive models. Interestingly, 8 PD-associated SNPs were also associated with age at onset of PD (P < 0.05) in dominant and recessive models. The SNP most significantly associated with PD and age at onset was rs17649641 (P = 0.015 and 0.021, respectively). Two-SNP haplotypes inferred from rs17563965 and rs17649641 also showed association with PD (P = 0.018) and age at onset (P = 0.026). These results provide further support for the role of MAPT in development of PD.
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Affiliation(s)
- K S Wang
- Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, PO Box 70259, Lamb Hall, Johnson City, TN 37614-1700, USA.
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Gasser T. Identifying PD-causing genes and genetic susceptibility factors: current approaches and future prospects. PROGRESS IN BRAIN RESEARCH 2010; 183:3-20. [PMID: 20696312 DOI: 10.1016/s0079-6123(10)83001-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Over the last years, a plethora of genetic findings have completely changed our views on the aetiology of Parkinson's disease (PD). Linkage studies and positional cloning strategies have identified mutations in a growing number of genes which cause monogenic autosomal-dominant or autosomal-recessive forms of the disorder. While these Mendelian forms of PD are relatively rare, high-throughput genotyping and sequencing technologies have more recently provided evidence that low-penetrance variants in at least some of these genes also play a direct role in the aetiology of the common sporadic disease. In addition, rare variants in other genes, such as the Gaucher's disease-associated glucocerebrosidase A, have also been found to be important risk factors at least in subgroups of patients. Thus, an increasingly complex network of genes contributing in different ways to disease risk and progression is emerging. These findings provide the 'genetic entry points' to identify molecular targets and readouts necessary to design rational disease-modifying treatments.
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Affiliation(s)
- Thomas Gasser
- Hertie Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, Tübingen, Germany.
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Poorkaj P, Raskind WH, Leverenz JB, Matsushita M, Zabetian CP, Samii A, Kim S, Gazi N, Nutt JG, Wolff J, Yearout D, Greenup JL, Steinbart EJ, Bird TD. A novel X-linked four-repeat tauopathy with Parkinsonism and spasticity. Mov Disord 2010; 25:1409-17. [PMID: 20629132 DOI: 10.1002/mds.23085] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
The parkinsonian syndromes comprise a highly heterogeneous group of disorders. Although 15 loci are linked to predominantly familial Parkinson's disease (PD), additional PD loci are likely to exist. We recently identified a multigenerational family of Danish and German descent in which five males in three generations presented with a unique syndrome characterized by parkinsonian features and variably penetrant spasticity for which X-linked disease transmission was strongly suggested (XPDS). Autopsy in one individual failed to reveal synucleinopathy; however, there was a significant four-repeat tauopathy in the striatum. Our objective was to identify the locus responsible for this unique parkinsonian disorder. Members of the XPDS family were genotyped for markers spanning the X chromosome. Two-point and multipoint linkage analyses were performed and the candidate region refined by analyzing additional markers. A multipoint LOD(max) score of 2.068 was obtained between markers DXS991 and DXS993. Haplotype examination revealed an approximately 20 cM region bounded by markers DXS8042 and DXS1216 that segregated with disease in all affected males and obligate carrier females and was not carried by unaffected at-risk males. To reduce the possibility of a false-positive linkage result, multiple loci and genes associated with other parkinsonian or spasticity syndromes were excluded. In conclusion, we have identified a unique X-linked parkinsonian syndrome with variable spasticity and four-repeat tau pathology, and defined a novel candidate gene locus spanning approximately 28 Mb from Xp11.2-Xq13.3.
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Affiliation(s)
- Parvoneh Poorkaj
- Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA.
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Wong AK, Marushchak DO, Gradinaru CC, Krull UJ. A mixed film composed of oligonucleotides and poly(2-hydroxyethyl methacrylate) brushes to enhance selectivity for detection of single nucleotide polymorphisms. Anal Chim Acta 2010; 661:103-10. [DOI: 10.1016/j.aca.2009.12.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2009] [Revised: 11/29/2009] [Accepted: 12/01/2009] [Indexed: 10/20/2022]
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Edwards TL, Scott WK, Almonte C, Burt A, Powell EH, Beecham GW, Wang L, Züchner S, Konidari I, Wang G, Singer C, Nahab F, Scott B, Stajich JM, Pericak-Vance M, Haines J, Vance JM, Martin ER. Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet 2010; 74:97-109. [PMID: 20070850 DOI: 10.1111/j.1469-1809.2009.00560.x] [Citation(s) in RCA: 372] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Parkinson disease (PD) is a chronic neurodegenerative disorder with a cumulative prevalence of greater than one per thousand. To date three independent genome-wide association studies (GWAS) have investigated the genetic susceptibility to PD. These studies implicated several genes as PD risk loci with strong, but not genome-wide significant, associations. In this study, we combined data from two previously published GWAS of Caucasian subjects with our GWAS of 604 cases and 619 controls for a joint analysis with a combined sample size of 1752 cases and 1745 controls. SNPs in SNCA (rs2736990, p-value = 6.7 x 10(-8); genome-wide adjusted p = 0.0109, odds ratio (OR) = 1.29 [95% CI: 1.17-1.42] G vs. A allele, population attributable risk percent (PAR%) = 12%) and the MAPT region (rs11012, p-value = 5.6 x 10(-8); genome-wide adjusted p = 0.0079, OR = 0.70 [95% CI: 0.62-0.79] T vs. C allele, PAR%= 8%) were genome-wide significant. No other SNPs were genome-wide significant in this analysis. This study confirms that SNCA and the MAPT region are major genes whose common variants are influencing risk of PD.
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Affiliation(s)
- Todd L Edwards
- John P. Hussman Institute for Human Genomics, University of Miami, FL 33136, USA
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Khandelwal PJ, Moussa CEH. The Relationship between Parkin and Protein Aggregation in Neurodegenerative Diseases. Front Psychiatry 2010; 1:15. [PMID: 21423426 PMCID: PMC3059628 DOI: 10.3389/fpsyt.2010.00015] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2010] [Accepted: 05/10/2010] [Indexed: 12/12/2022] Open
Abstract
The most prominent changes in neurodegenerative diseases are protein accumulation and inclusion formation. Several neurodegenerative diseases, including Alzheimer's, the Synucleinopathies and Tauopathies share several overlapping clinical symptoms manifest in Parkinsonism, cognitive decline and dementia. As degeneration progresses in the disease process, clinical symptoms suggest convergent pathological pathways. Biochemically, protein cleavage, ubiquitination and phosphorylation seem to play fundamental roles in protein aggregation, inclusion formation and inflammatory responses. In the following we provide a synopsis of the current knowledge about protein accumulation and astrogliosis as a common denominator in neurodegenerative diseases, and we propose insights into protein degradation and anti-inflammation. We review the E3-ubiquitin ligase and other possible functions of parkin as a suppressant of inflammatory signs and a strategy to clear amyloid proteins in neurodegenerative diseases.
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Affiliation(s)
- Preeti J Khandelwal
- Department of Neuroscience, Georgetown University Medical Center Washington, DC, USA
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43
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Abstract
Over the past few years, genetic findings have changed our views on the molecular pathogenesis of Parkinson disease (PD), as mutations in a growing number of genes have been found to cause monogenic forms of the disorder. These mutations cause neuronal dysfunction and neurodegeneration either by a toxic gain of function, as in the case of the dominant forms of monogenic PD caused by mutations in the genes for alpha-synuclein or LRRK2, or by a loss of an intrinsic protective function, as is likely for the recessive PD genes parkin (PRKN), PINK1 and DJ-1. Evidence is emerging that at least some of the pathways uncovered in the rare monogenic forms of PD may play a direct role in the aetiology of the common sporadic disorder and that variants of the respective genes contribute to the risk of developing the disease. These findings will allow the search for new treatment strategies that focus on the underlying molecular pathophysiology, rather than simply on ameliorating symptoms.
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44
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Pei YF, Zhang L, Liu J, Deng HW. Multivariate association test using haplotype trend regression. Ann Hum Genet 2009; 73:456-64. [PMID: 19489754 DOI: 10.1111/j.1469-1809.2009.00527.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Genetic association analyses with haplotypes may be more powerful than analyses with single markers, under certain conditions. Furthermore, simultaneously considering multiple correlated traits may make use of additional information that would not be considered when analyzing individual traits. In this study, we propose a haplotype based test of association for multivariate quantitative traits in unrelated samples. Specifically, we extend a population based haplotype trend regression (HTR) approach to multivariate scenarios. We mainly focused on bivariate HTR, and the simulation results showed that the proposed method had correct pre-specified type-I error rates. The power of the proposed method was largely influenced by the size and source of correlation between variables, being greatest when correlation of a specific gene was opposite in sign to the residual correlation.
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Affiliation(s)
- Yu-Fang Pei
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, P. R. China
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Gao X, Martin ER, Liu Y, Mayhew G, Vance JM, Scott WK. Genome-wide linkage screen in familial Parkinson disease identifies loci on chromosomes 3 and 18. Am J Hum Genet 2009; 84:499-504. [PMID: 19327735 DOI: 10.1016/j.ajhg.2009.03.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2008] [Revised: 03/02/2009] [Accepted: 03/09/2009] [Indexed: 10/21/2022] Open
Abstract
Parkinson disease (PD) is a complex, multifactorial neurodegenerative disease with substantial evidence for genetic risk factors. We conducted a genome-wide linkage screen of 5824 single-nucleotide polymorphisms in 278 families of European, non-Hispanic descent to localize regions that harbor susceptibility loci for PD. By using parametric and nonparametric linkage analyses and allowing for genetic heterogeneity among families, we found two loci for PD. Significant evidence for linkage was detected on chromosome 18q11 (maximum lod score [MLOD] = 4.1) and suggestive evidence for linkage was obtained on chromosome 3q25 (MLOD = 2.5). These results were strongest in families not previously screened for linkage, and simulation studies suggest that these findings are likely due to locus heterogeneity rather than random statistical error. The finding of two loci (one highly statistically significant) suggests that additional PD susceptibility genes might be identified through targeted candidate gene studies in these regions.
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Devine MJ, Lewis PA. Emerging pathways in genetic Parkinson's disease: tangles, Lewy bodies and LRRK2. FEBS J 2009; 275:5748-57. [PMID: 19021752 DOI: 10.1111/j.1742-4658.2008.06707.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The last decade has seen clear links emerge between the genetic determinants and neuropathological hallmarks of parkinsonism and dementia, notably with the discovery of mutations in alpha-synuclein and tau. Following the description of mutations in LRRK2 linked to Parkinson's disease, characterized by variable pathology including either alpha-synuclein or tau deposition, it has been suggested that LRRK2 functions as an upstream regulator of Parkinson's disease pathogenesis. This minireview explores this model, in the context of our current understanding of the biochemistry of LRRK2, alpha-synuclein and tau.
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Affiliation(s)
- Michael J Devine
- Department of Clinical Neuroscience, Imperial College London, UK
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47
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Peuralinna T, Oinas M, Polvikoski T, Paetau A, Sulkava R, Niinistö L, Kalimo H, Hernandez D, Hardy J, Singleton A, Tienari PJ, Myllykangas L. Neurofibrillary tau pathology modulated by genetic variation of alpha-synuclein. Ann Neurol 2008; 64:348-52. [PMID: 18661559 DOI: 10.1002/ana.21446] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
We analyzed whether genetic variation of alpha-synuclein modulates the extent of neuropathological changes in a population-based autopsied sample of 272 elderly Finns. None of the 11 markers was associated with the extent of neocortical beta-amyloid pathology. The intron 4 marker rs2572324 was associated with the extent of neurofibrillary pathology (p = 0.0006, permuted p = 0.004; Braak stages IV-VI vs 0-II). The same variant also showed a trend for association with neocortical Lewy-related pathology. These results suggest for the first time that variation of alpha-synuclein modulates neurofibrillary tau pathology and support the recent observations of an interaction of alpha-synuclein and tau in neurodegeneration.
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Affiliation(s)
- Terhi Peuralinna
- Molecular Neurology Programme, Biomedicum, University of Helsinki, Helsinki, Finland
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Canu E, Boccardi M, Ghidoni R, Benussi L, Testa C, Pievani M, Bonetti M, Binetti G, Frisoni GB. H1 haplotype of the MAPT gene is associated with lower regional gray matter volume in healthy carriers. Eur J Hum Genet 2008; 17:287-94. [PMID: 18854867 DOI: 10.1038/ejhg.2008.185] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The microtubule-associated protein Tau (MAPT) gene codes for the protein Tau that is involved in the pathogenesis of neurodegenerative diseases. Recent studies have detected an over-representation of the H1 haplotype of the MAPT gene in neurodegenerative disorders such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia (FTD) and Parkinson's disease (PD), whereas the H2 haplotype has been found to be related to familial FTD. We aimed to investigate the association between MAPT haplotype status and brain morphology in healthy adults. A total of 150 healthy subjects underwent 3D high-resolution magnetic resonance (MR). MR images were processed following an optimized protocol to perform the Voxel-based morphometry (VBM) comparisons of the gray matter (GM) in H1 carriers (n=141) in contrast to H2H2 homozygous (n=9), and H1H1 homozygous (n=85) in contrast to H2 carriers (n=65). The threshold for statistical significance was 0.005 uncorrected. Opposite comparisons were also carried out. The groups had similar demographic and cognitive features. Compared with H2H2, the H1 carriers showed up to 19% smaller GM volume in the head of the right caudate nucleus, in the right middle frontal gyrus, in the left insula and orbito-frontal cortex, and in the inferior temporal and inferior cerebellar lobes, bilaterally. Compared with all H2 carriers, H1H1 displayed lower GM in the same regions, but the effect was smaller (5%), possibly due to a dilution effect by H1 in the H2 carriers group. The data suggest that H1 haplotype is associated with a particular cerebral morphology that may increase the susceptibility of the healthy carriers to develop neurodegenerative diseases such as sporadic tauopathies.
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Affiliation(s)
- Elisa Canu
- LENITEM Laboratory of Epidemiology, Neuroimaging, and Telemedicine, IRCCS Centro S Giovanni di Dio-FBF, Brescia, Italy
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Moussa CEH. Parkin attenuates wild-type tau modification in the presence of beta-amyloid and alpha-synuclein. J Mol Neurosci 2008; 37:25-36. [PMID: 18561034 DOI: 10.1007/s12031-008-9099-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2008] [Accepted: 05/06/2008] [Indexed: 12/24/2022]
Abstract
Changes in tau (tau) metabolism comprise important pathological landmarks in the tauopathies with parkinsonism as well as Parkinson's disease and Alzheimer's disease. Mutations in the parkin gene are associated with Parkinson's disease. Deposits of amyloid proteins, including Abeta and alpha-synuclein coexist in the brains of patients with dementia with Lewy bodies; however, it is not known how either of them interacts with tau to provoke neurofibrillary tangle formation across the tauopathies. Here, we show a role for parkin against tau pathology in the presence of intracellular Abeta or alpha-synuclein. Parkin attenuates four-repeat human tau, but not mutant P301L, hyperphosphorylation in the presence of intracellular Abeta(1-42), or alpha-synuclein and decreases GSK-3beta activity in amyloid-stressed M17 human neuroblastoma cells. These data suggest that parkin may counteract the alteration of tau metabolism in certain neurodegenerative diseases with tau cytopathy and parkinsonism.
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Affiliation(s)
- Charbel E-H Moussa
- Department of Biochemistry, Molecular and Cell Biology, Georgetown University Medical Center, The New Research Building, Room WP26B, 3970 Reservoir Rd, NW., Washington, DC 20007, USA.
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50
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Sánchez-Juan P, Bishop MT, Green A, Giannattasio C, Arias-Vasquez A, Poleggi A, Knight RSG, van Duijn CM. No evidence for association between tau gene haplotypic variants and susceptibility to Creutzfeldt-Jakob disease. BMC MEDICAL GENETICS 2007; 8:77. [PMID: 18072964 PMCID: PMC2235832 DOI: 10.1186/1471-2350-8-77] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2007] [Accepted: 12/11/2007] [Indexed: 11/10/2022]
Abstract
BACKGROUND A polymorphism at codon 129 of the prion protein gene (PRNP) is the only well-known genetic risk factor for Creutzfeldt-Jakob disease (CJD). However, there is increasing evidence that other loci outside the PRNP open reading frame might play a role in CJD aetiology as well. METHODS We studied tau protein gene (MAPT) haplotypic variations in a population of sporadic and variant CJD patients. We tested 6 MAPT haplotype tagging SNPs (htSNPs) in a Dutch population-based sample of sporadic CJD (sCJD) patients and a cognitively normal control group of similar age distribution. We genotyped the same polymorphisms in two other sample groups of sCJD cases from Italy and the UK. In addition, we compared MAPT haplotypes between sCJD and variant CJD (vCJD) patients. RESULTS Single locus and haplotype analyses did not detect any significant difference between sCJD cases and controls. When we compared MAPT haplotypes between sCJD and variant CJD (vCJD) patients, we found that two of them were represented differently (H1f: 8% in sCJD versus 2% in vCJD; H1j:1% in sCJD versus 7% in vCJD). However, these two haplotypes were rare in both groups of patients, and taking the small sample sizes into account, we cannot exclude that the differences are due to chance. None of the p-values remained statistically significant after applying a multiple testing correction. CONCLUSION Our study shows no evidence for an association between MAPT gene variations and sCJD, and some weak evidence for an association to vCJD.
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Affiliation(s)
- Pascual Sánchez-Juan
- Institute for Formation and Research of the Fundación Marqués de Valdecilla (IFIMAV), Santander, Spain.
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