Dataset Information

MAPT haplotype diversity in multiple system atrophy.

ABSTRACT: Multiple system atrophy (MSA) is a rare progressive neurodegenerative disorder. MSA was originally considered exclusively sporadic but reports of association with genes such as SNCA, COQ2 and LRRK2 have demonstrated that there is a genetic contribution to the disease. MAPT has been associated with several neurodegenerative diseases and we previously reported a protective association of the MAPT H2 haplotype with MSA in 61 pathologically confirmed cases.In the present study, we assessed the full MAPT haplotype diversity in MSA patients using six MAPT tagging SNPs. We genotyped a total of 127 pathologically confirmed MSA cases, 86 patients with clinically diagnosed MSA and 1312 controls.We identified four significant association signals in our pathologically confirmed cases, two from the protective haplotypes H2 (MSA:16.2%,22.7%, p = 0.024) and H1E (MSA:3.0%,9.0%, p = 0.014), and two from the rare risk haplotypes H1x (MSA:3.7%,1.3%, p = 0.030) and H1J (MSA:3.0%,0.9%, p = 0.021). We evaluated the association of MSA subtypes with the common protective H2 haplotype and found a significant difference with controls for MSA patients with some degree of MSA-C (MSA-C or MSA-mixed), for whom H2 occurred in only 8.6% of patients in our pathologically confirmed series (P < 0.0001).Our findings provide further evidence that MAPT variation is associated with risk of MSA. Interestingly, our results suggest a greater effect size in the MSA-C compared to MSA-P for H2. Additional genetic studies in larger pathologically confirmed MSA series and meta-analytic studies will be needed to fully assess the role of MAPT and other genes in MSA.

SUBMITTER: Labbe C

PROVIDER: S-EPMC5007155 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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MAPT haplotype diversity in multiple system atrophy.

Labbé Catherine C Heckman Michael G MG Lorenzo-Betancor Oswaldo O Murray Melissa E ME Ogaki Kotaro K Soto-Ortolaza Alexandra I AI Walton Ronald L RL Fujioka Shinsuke S Koga Shunsuke S Uitti Ryan J RJ van Gerpen Jay A JA Petersen Ronald C RC Graff-Radford Neill R NR Younkin Steven G SG Boeve Bradley F BF Cheshire William P WP Low Phillip A PA Sandroni Paola P Coon Elizabeth A EA Singer Wolfgang W Wszolek Zbigniew K ZK Dickson Dennis W DW Ross Owen A OA

Parkinsonism & related disorders 20160616

<h4>Introduction</h4>Multiple system atrophy (MSA) is a rare progressive neurodegenerative disorder. MSA was originally considered exclusively sporadic but reports of association with genes such as SNCA, COQ2 and LRRK2 have demonstrated that there is a genetic contribution to the disease. MAPT has been associated with several neurodegenerative diseases and we previously reported a protective association of the MAPT H2 haplotype with MSA in 61 pathologically confirmed cases.<h4>Methods</h4>In the ...[more]

PMID: 27374978

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Project description:Multiple system atrophy (MSA) is an orphan, fatal, adult-onset neurodegenerative disorder of uncertain etiology that is clinically characterized by various combinations of parkinsonism, cerebellar, autonomic, and motor dysfunction. MSA is an ?-synucleinopathy with specific glioneuronal degeneration involving striatonigral, olivopontocerebellar, and autonomic nervous systems but also other parts of the central and peripheral nervous systems. The major clinical variants correlate with the morphologic phenotypes of striatonigral degeneration (MSA-P) and olivopontocerebellar atrophy (MSA-C). While our knowledge of the molecular pathogenesis of this devastating disease is still incomplete, updated consensus criteria and combined fluid and imaging biomarkers have increased its diagnostic accuracy. The neuropathologic hallmark of this unique proteinopathy is the deposition of aberrant ?-synuclein in both glia (mainly oligodendroglia) and neurons forming glial and neuronal cytoplasmic inclusions that cause cell dysfunction and demise. In addition, there is widespread demyelination, the pathogenesis of which is not fully understood. The pathogenesis of MSA is characterized by propagation of misfolded ?-synuclein from neurons to oligodendroglia and cell-to-cell spreading in a "prion-like" manner, oxidative stress, proteasomal and mitochondrial dysfunction, dysregulation of myelin lipids, decreased neurotrophic factors, neuroinflammation, and energy failure. The combination of these mechanisms finally results in a system-specific pattern of neurodegeneration and a multisystem involvement that are specific for MSA. Despite several pharmacological approaches in MSA models, addressing these pathogenic mechanisms, no effective neuroprotective nor disease-modifying therapeutic strategies are currently available. Multidisciplinary research to elucidate the genetic and molecular background of the deleterious cycle of noxious processes, to develop reliable biomarkers and targets for effective treatment of this hitherto incurable disorder is urgently needed.

Dataset Information

MAPT haplotype diversity in multiple system atrophy.

Publications

MAPT haplotype diversity in multiple system atrophy.

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