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Cyclin-G-associated kinase modifies α-synuclein expression levels and toxicity in Parkinson's disease: Results from the GenePD Study

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Abstract

Although family history is awell-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 α-synuclein is common to nearly all patients, implicating pathways that influence α-synuclein in PD pathogenesis. We report a genome-wide significant association (P = 3.97 × 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 α-synuclein expression, a known cause of early onset PD. Functional knockdown of GAK in cell culture causes a significant increase in toxicity when α-synuclein is over-expressed. Furthermore, knockdown of GAK in rat primary neurons expressing the A53T mutation of α-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 a-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 α-synuclein expression and toxicity, suggests that the protein is an attractive therapeutic target for the treatment of PD. © The Author 2011. Published by Oxford University Press. All rights reserved.

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Dumitriu, A., Pacheco, C. D., Wilk, J. B., Strathearn, K. E., Latourelle, J. C., Goldwurm, S., … Myers, R. H. (2011). Cyclin-G-associated kinase modifies α-synuclein expression levels and toxicity in Parkinson’s disease: Results from the GenePD Study. Human Molecular Genetics, 20(8), 1478–1487. https://doi.org/10.1093/hmg/ddr026

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