Journal
HUMAN MOLECULAR GENETICS
Volume 20, Issue 8, Pages 1478-1487Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddr026
Keywords
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Funding
- Robert P. & Judith N. Goldberg Foundation
- Bumpus Foundation
- Howard Hughes Collaborative Innovation Award
- Italian Telethon [GTB07001]
- Fondazione Grigioni per il Morbo di Parkinson
- Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine
- Boston Medical Center
- National Institute on Aging [P30 AG19610]
- Arizona Department of Health Services [211002]
- Arizona Biomedical Research Commission [4001, 0011, 05-901]
- Michael J. Fox Foundation
- PHS [R24 MH 068855]
- NINDS/NIMH
- National Multiple Sclerosis Society, Department of Veterans
- [R01-NS036711]
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Although family history is a well-established risk factor for Parkinson's disease (PD), fewer than 5% of PD cases can be attributed to known genetic mutations. The etiology for the remainder of PD cases is unclear; however, neuronal accumulation of the protein alpha-synuclein is common to nearly all patients, implicating pathways that influence alpha-synuclein in PD pathogenesis. We report a genome-wide significant association ( P = 3.97 x 10(-8)) between a polymorphism, rs1564282, in the cyclin-G-associated kinase (GAK) gene and increased PD risk, with a meta-analysis odds ratio of 1.48. This association result is based on the meta-analysis of three publicly available PD case-control genome-wide association study and genotyping from a new, independent Italian cohort. Microarray expression analysis of post-mortem frontal cortex from PD and control brains demonstrates a significant association between rs1564282 and higher alpha-synuclein expression, a known cause of early onset PD. Functional knockdown of GAK in cell culture causes a significant increase in toxicity when alpha-synuclein is over-expressed. Furthermore, knockdown of GAK in rat primary neurons expressing the A53T mutation of a-synuclein, a well-established model for PD, decreases cell viability. These observations provide evidence that GAK is associated with PD risk and suggest that GAK and alpha-synuclein interact in a pathway involved in PD pathogenesis. The GAK protein, a serine/threonine kinase, belongs to a family of proteins commonly targeted for drug development. This, combined with GAK's observed relationship to the levels of alpha-synuclein expression and toxicity, suggests that the protein is an attractive therapeutic target for the treatment of PD.
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