Department of Neurology, Boston University School of Medicine, 72 East Concord Street, E-304, Boston, MA 02118, USA.
Hum Mol Genet. 2011 Apr 15;20(8):1478-87. doi: 10.1093/hmg/ddr026. Epub 2011 Jan 21.
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.
虽然家族史是帕金森病（PD）的一个既定危险因素，但不到 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，几乎所有患者的神经元中都有α-突触核蛋白的积累，这表明影响 PD 发病机制的α-突触核蛋白途径。我们报告了细胞周期蛋白 G 相关激酶（GAK）基因中的 rs1564282 多态性与 PD 风险增加之间具有全基因组显著关联（P=3.97×10(-8))，meta 分析的优势比为 1.48。该关联结果基于三个公开的 PD 病例对照全基因组关联研究的荟萃分析和来自新的独立意大利队列的基因分型。PD 和对照大脑死后额皮质的微阵列表达分析表明，rs1564282 与α-突触核蛋白表达升高之间存在显著关联，α-突触核蛋白是早发性 PD 的已知原因。细胞培养中 GAK 的功能敲低会导致α-突触核蛋白过表达时毒性显著增加。此外，在表达 A53T 突变的α-突触核蛋白的大鼠原代神经元中敲低 GAK，可降低细胞活力。这些观察结果提供了证据表明 GAK 与 PD 风险相关，并表明 GAK 和α-突触核蛋白在涉及 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，属于通常被靶向开发药物的蛋白质家族。这一点，加上 GAK 与α-突触核蛋白表达和毒性水平的观察到的关系，表明该蛋白是治疗 PD 的有吸引力的治疗靶标。
