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

PROJECT NARRATIVE 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS078086-01
Application #
8272234
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Sutherland, Margaret L
Project Start
2012-04-01
Project End
2017-01-31
Budget Start
2012-04-01
Budget End
2013-01-31
Support Year
1
Fiscal Year
2012
Total Cost
$339,063
Indirect Cost
$120,313
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
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Fujioka, Shinsuke; Algom, Avi A; Murray, Melissa E et al. (2016) Tremor in progressive supranuclear palsy. Parkinsonism Relat Disord 27:93-7
Hassan, Anhar; Heckman, Michael G; Ahlskog, J E et al. (2016) Association of Parkinson disease age of onset with DRD2, DRD3 and GRIN2B polymorphisms. Parkinsonism Relat Disord 22:102-5
Heckman, Michael G; Soto-Ortolaza, Alexandra I; Sanchez Contreras, Monica Y et al. (2016) LRRK2 variation and dementia with Lewy bodies. Parkinsonism Relat Disord 31:98-103
Labbé, Catherine; Heckman, Michael G; Lorenzo-Betancor, Oswaldo et al. (2016) MAPT haplotype H1G is associated with increased risk of dementia with Lewy bodies. Alzheimers Dement 12:1297-1304
Konno, Takuya; Ross, Owen A; Wharen, Robert E et al. (2016) Deep brain stimulation for levodopa-refractory benign tremulous parkinsonism. Neurol Neurochir Pol 50:383-6
Labbé, Catherine; Lorenzo-Betancor, Oswaldo; Ross, Owen A (2016) Epigenetic regulation in Parkinson's disease. Acta Neuropathol 132:515-30
Konno, Takuya; Ross, Owen A; Puschmann, Andreas et al. (2016) Autosomal dominant Parkinson's disease caused by SNCA duplications. Parkinsonism Relat Disord 22 Suppl 1:S1-6
Guerreiro, Rita; Escott-Price, Valentina; Darwent, Lee et al. (2016) Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases. Neurobiol Aging 38:214.e7-10

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