Mutations within the MAPT gene encoding the microtubule-associated protein tau result in the clinical phenotype of frontotemporal dementia with parkinsonism or progressive supranuclear palsy (PSP) both displaying predominant tau pathology at autopsy. Common variants at the MAPT locus further define two non- recombining MAPT haplotypes (MAPT H1 and H2) resulting from an ancient inversion. Recent genome-wide association studies have implicated MAPT H1 as a significant risk factor for both Parkinson's disease (PD) and PSP;however preliminary sub-haplotype analyses suggest that different genetic variants on the MAPT H1 haplotype associate with each of these parkinsonian disorders. It currently remains unclear which variation at the MAPT locus is responsible for the risk and what is the underlying pathomechanism of disease. This project sets out to resolve the disease-associated genetic variation within the MAPT locus for both PD and PSP patients, to characterize the prevalence and effect size and to determine the functional consequence.
The Specific Aims are focused on 1) identification of genetic variants in the MAPT genomic region through next-generation sequencing of 350 PD, 350 PSP and 350 controls using a DNA pooling strategy;2) genetic association analyses of common and rare variants in MAPT in extensive PD and PSP case-control populations;and 3) study of the effect of MAPT variants on MAPT transcription, translation and alternative splicing in vitro and in human brain. The proposed studies are relevant to fully appreciate the contribution of common and rare variants in MAPT to the development of parkinsonian disorders and will contribute to a better understanding of the disease mechanism associated with tau dysfunction in PD and PSP.

Public Health Relevance

This proposal is designed to determine the full contribution of common and rare variants in MAPT to the development of the two most common parkinsonian disorders, PD and PSP. The proposed studies will contribute to our understanding of and our ability to treat patients with parkinsonism through improved patient diagnosis, the ability to develop novel etiologic disease models and an increased understanding of the MAPT associated pathomechanism(s), which may ultimately inform possible therapeutic strategies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Sutherland, Margaret L
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Mayo Clinic Jacksonville
United States
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Labbé, Catherine; Ross, Owen A (2014) Association studies of sporadic Parkinson's disease in the genomic era. Curr Genomics 15:2-10
Shannon, Barbara; Soto-Ortolaza, Alexandra; Rayaprolu, Sruti et al. (2014) Genetic variation of the retromer subunits VPS26A/B-VPS29 in Parkinson's disease. Neurobiol Aging 35:1958.e1-2
Ogaki, Kotaro; Ross, Owen A (2014) Chromosome 22q11.2 deletion may contain a locus for recessive early-onset Parkinson's disease. Parkinsonism Relat Disord 20:945-6
Kouri, Naomi; Carlomagno, Yari; Baker, Matthew et al. (2014) Novel mutation in MAPT exon 13 (p.N410H) causes corticobasal degeneration. Acta Neuropathol 127:271-82
Lorenzo-Betancor, Oswaldo; Ogaki, Kotaro; Soto-Ortolaza, Alexandra et al. (2014) Analysis of nuclear export sequence regions of FUS-Related RNA-binding proteins in essential tremor. PLoS One 9:e111989
Heckman, Michael G; Schottlaender, Lucia; Soto-Ortolaza, Alexandra I et al. (2014) LRRK2 exonic variants and risk of multiple system atrophy. Neurology 83:2256-61
Ogaki, Kotaro; Fujioka, Shinsuke; Heckman, Michael G et al. (2014) Analysis of COQ2 gene in multiple system atrophy. Mol Neurodegener 9:44
Mulroy, Eoin; McCarthy, Allan; Lynch, Tim et al. (2014) Asymmetrical leg atrophy in levodopa-responsive dystonia due to a novel GTP cyclohydrolase mutation. Mov Disord 29:425-6
Theuns, Jessie; Verstraeten, Aline; Sleegers, Kristel et al. (2014) Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease. Neurology 83:1906-13
Bras, Jose; Guerreiro, Rita; Darwent, Lee et al. (2014) Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies. Hum Mol Genet 23:6139-46

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