Cyclin-G-associated kinase modifies α-synuclein expression levels and toxicity in Parkinson's disease: results from the GenePD Study
Cyclin-G-associated kinase modifies α-synuclein expression levels and toxicity in Parkinson's disease: results from the GenePD Study
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DOI：
10.1093/hmg/ddr026
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发表时间：
2011-04-15
影响因子：
3.5
通讯作者：
Myers, Richard H.
中科院分区：
文献类型：
--
作者：
Dumitriu, Alexandra;Pacheco, Chris D.;Myers, Richard H.
尽管家族史是帕金森病 (PD) 的一个公认的危险因素，但只有不到 5% 的 PD 病例可归因于已知的基因突变。其余 PD 病例的病因尚不清楚；然而，几乎所有患者都存在 α-突触核蛋白的神经元积聚现象，这表明在 PD 发病机制中存在影响 α-突触核蛋白的途径。我们报告了细胞周期蛋白 G 相关激酶 (GAK) 基因中的多态性 rs1564282 与 PD 风险增加之间存在全基因组显着关联 (P = 3.97 x 10(-8))，荟萃分析优势比为 1.48。该关联结果基于三项公开的 PD 病例对照全基因组关联研究的荟萃分析以及来自一个新的独立意大利队列的基因分型。对 PD 和对照大脑死后额叶皮层的微阵列表达分析表明 rs1564282 与较高的 α-突触核蛋白表达之间存在显着关联，α-突触核蛋白表达是早发性 PD 的已知原因。当 α-突触核蛋白过度表达时，细胞培养中 GAK 的功能性敲除会导致毒性显着增加。此外，在表达α-突触核蛋白A53T突变的大鼠原代神经元（一种完善的PD模型）中敲低GAK会降低细胞活力。这些观察结果提供了 GAK 与 PD 风险相关的证据，并表明 GAK 和 α-突触核蛋白在参与 PD 发病机制的途径中相互作用。 GAK 蛋白是一种丝氨酸/苏氨酸激酶，属于药物开发常用目标蛋白家族。这与观察到的 GAK 与 α-突触核蛋白表达水平和毒性的关系相结合，表明该蛋白是治疗 PD 的一个有吸引力的治疗靶点。
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.