Cyclin-G-associated kinase modifies α-synuclein expression levels and toxicity in Parkinson's disease: results from the GenePD Study.
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 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 α-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.
Department of Neurology, Boston University School of Medicine, 72 East Concord Street, E-304, Boston, MA 02118, USA.
Alexandra
A
Dumitriu
Chris D
CD
Pacheco
Jemma B
JB
Wilk
Katherine E
KE
Strathearn
Jeanne C
JC
Latourelle
Stefano
S
Goldwurm
Gianni
G
Pezzoli
Jean-Christophe
JC
Rochet
Susan
S
Lindquist
Richard H
RH
Myers
D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D002402:Cathepsin D / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; D051844:alpha-Synuclein; C486325:GAK protein, human; D017346:Protein Serine-Threonine Kinases; D000263:Adenylate Kinase; C533922:CTSD protein, human; D002402:Cathepsin D
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