The 4p16.3 Parkinson Disease Risk Locus Is Associated with GAK Expression and Genes Involved with the Synaptic Vesicle Membrane.
The 4p16.3 Parkinson Disease Risk Locus Is Associated with GAK Expression and Genes Involved with the Synaptic Vesicle Membrane.
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DOI：
10.1371/journal.pone.0160925
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Myers RH
中科院分区：
文献类型：
--
作者：
Nagle MW;Latourelle JC;Labadorf A;Dumitriu A;Hadzi TC;Beach TG;Myers RH
全基因组关联研究发现，在帕金森病(PD)的前三个危险基因中，位于4p16.3的GAK/DGKQ/IDUA区域是帕金森病(PD)的主要易感基因，但其具体基因和发病机制尚不清楚。在这里，我们报告了含有GAK的3‘分子筛蛋白结合域的转录本，通过RNA深度测序在死后的人脑组织中鉴定为在帕金森病中表达增加。此外，4p16.3PD Gwas风险SNPs的携带者表现出其中一种转录物GAK25(GENCODE转录本009)的表达减少，该转录本与突触囊泡膜中功能基因的表达相关。综上所述，这些发现为GAK-clathrin结合和J-结构域转录本对PD致病性的影响以及GAK在调节PD的突触功能中的作用提供了强有力的证据。
Genome-wide association studies (GWAS) have identified the GAK/DGKQ/IDUA region on 4p16.3 among the top three risk loci for Parkinson’s disease (PD), but the specific gene and risk mechanism are unclear. Here, we report transcripts containing the 3’ clathrin-binding domain of GAK identified by RNA deep-sequencing in post-mortem human brain tissue as having increased expression in PD. Furthermore, carriers of 4p16.3 PD GWAS risk SNPs show decreased expression of one of these transcripts, GAK25 (Gencode Transcript 009), which correlates with the expression of genes functioning in the synaptic vesicle membrane. Together, these findings provide strong evidence for GAK clathrin-binding- and J-domain transcripts’ influence on PD pathogenicity, and for a role for GAK in regulating synaptic function in PD.