The effect of the cyclin G-associated kinase on the pathogenesis of Parkinson's disease
Nagle, Michael William
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Parkinson's Disease (PD) is the second most common neurodegenerative disorder, clinically characterized by severe motor impairment and pathologically characterized by progressive loss of the dopaminergic neurons of the substantia nigra pars compacta (SNpc) as well as the formation of cellular aggregate deposits called Lewy Bodies. While some advances have been made in understanding the molecular underpinnings of the disorder, the molecular implications of common genetic factors increasing risk for PD have not been adequately studied. First identified by GWA studies in 2009, the GAK/DGKQ/IDUA region on chromosome 4p16.3 shows significant genetic association to risk for PD, and the GAK protein has been shown to be associated with the primary component of Lewy Bodies, a-synuclein. In order to determine which gene in the 4p16.3 region may account for the genetic association to PD and to understand the molecular consequences of that association, post-mortem cortical brain tissue from 29 PD and 49 control patients was RNA-sequenced and differential exon usage in the context of disease and risk variant carrier status was analyzed. Exons in the 3' region of GAK were found to be associated to case status, and notably exon 25 expression in GAK was associated with both case status and the risk variant. This exon was further observed to be associated to several genes previously shown to interact with GAK, including SNCA, which codes for a-synuclein. As a proxy for expression of the 3' region of GAK, exon 25 was assessed for genome-wide association, and genes showing association to the exon were involved in pathways related to synaptic transmission and neuronal function. In order to validate these findings, microarray analysis of primary rat cortical neurons in which GAK expression was reduced by shRNA transduction was performed. GAK expression in rat neurons was significantly inversely correlated to endogenous SNCA expression, and also exhibited association to pathways involved in synaptic transmission and mitochondrial function. Together, these findings suggest aberrant GAK expression related to genetic risk to be an important factor in the pathogenesis of PD through GAK's influence on SNCA expression and through dysregulation of important neuronal pathways.