This proposal seeks to discover a new gene(s) within a candidate region on chromosome 1p that modifies PD susceptibility and/or age at onset. The characterization of such a gene, and the pathways in which it participates, will further our understanding of the molecular events that lead to selective neurodegeneration in PD. This knowledge might serve to identify novel therapeutic targets which could be used to prevent and better treat the disease.

Public Health Relevance

Parkinson's disease (PD) affects 1-2% of the population over 60 years of age and thus constitutes a major problem in public health. Current treatment strategies are only palliative and a better understanding of the molecular mechanisms underlying PD is necessary in order to develop more definitive neuroprotective therapies. Human genetic studies are a valuable tool in this endeavor. A new candidate region for PD was recently identified on chromosome 1p in two independent linkage studies. However, the identity of the disease gene(s) within this region has not yet been determined. In this application, we propose to fine-map the candidate interval using 7,600 single nucleotide polymorphisms (SNPs) in 300 multiplex PD families recruited from across the United States. FBAT- based methods will be utilized to identify SNPs which modify PD risk or age at onset. Exploratory analyses will be undertaken to test for gene x environment interactions. We will then validate markers which meet a pre-defined significance threshold in an independent case control sample of 2,000 subjects. Finally, an extensive bioinformatics analysis will be performed to assemble a list of putative functional risk variants which will subsequently be tested for effects on gene expression and/or protein function via in vitro assays. This work has the potential to discover a new disease gene(s) which could provide important insights into the pathogenesis of PD that ultimately translate into improved strategies for diagnosis, prevention, and treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065070-03
Application #
8119068
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Sutherland, Margaret L
Project Start
2009-09-30
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
3
Fiscal Year
2011
Total Cost
$529,213
Indirect Cost
Name
University of Washington
Department
Neurology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Liu, Shu-Ying; Wile, Daryl J; Fu, Jessie Fanglu et al. (2018) The effect of LRRK2 mutations on the cholinergic system in manifest and premanifest stages of Parkinson's disease: a cross-sectional PET study. Lancet Neurol 17:309-316
Blue, Elizabeth E; Bis, Joshua C; Dorschner, Michael O et al. (2018) Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project. Dement Geriatr Cogn Disord 45:1-17
Wile, Daryl J; Agarwal, Pankaj A; Schulzer, Michael et al. (2017) Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies. Lancet Neurol 16:351-359
Mata, Ignacio F; Johnson, Catherine O; Leverenz, James B et al. (2017) Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease. Neurobiol Aging 56:211.e1-211.e7
Irwin, David J; Grossman, Murray; Weintraub, Daniel et al. (2017) Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis. Lancet Neurol 16:55-65
Yang, Li; Stewart, Tessandra; Shi, Min et al. (2017) An alpha-synuclein MRM assay with diagnostic potential for Parkinson's disease and monitoring disease progression. Proteomics Clin Appl 11:
Cornejo-Olivas, Mario; Torres, Luis; Velit-Salazar, Mario R et al. (2017) Variable frequency of LRRK2 variants in the Latin American research consortium on the genetics of Parkinson's disease (LARGE-PD), a case of ancestry. NPJ Parkinsons Dis 3:19
Gatto, Emilia M; Allegri, Ricardo F; Da Prat, Gustavo et al. (2017) Intrafamilial variable phenotype including corticobasal syndrome in a family with p.P301L mutation in the MAPT gene: first report in South America. Neurobiol Aging 53:195.e11-195.e17
Mata, Ignacio F; Leverenz, James B; Weintraub, Daniel et al. (2016) GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. Mov Disord 31:95-102
Shi, Min; Kovac, Andrej; Korff, Ane et al. (2016) CNS tau efflux via exosomes is likely increased in Parkinson's disease but not in Alzheimer's disease. Alzheimers Dement 12:1125-1131

Showing the most recent 10 out of 61 publications