Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia.
Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Nedlands, WA, Australia.
Sci Rep. 2021 Mar 18;11(1):6363. doi: 10.1038/s41598-021-85510-0.
Abnormal mitochondrial function is a key process in the pathogenesis of Parkinson's disease (PD). The central pore-forming protein TOM40 of the mitochondria is encoded by the translocase of outer mitochondrial membrane 40 homologue gene (TOMM40). The highly variant '523' poly-T repeat is associated with age-related cognitive decline and age of onset in Alzheimer's disease, but whether it plays a role in modifying the risk or clinical course of PD it yet to be elucidated. The TOMM40 '523' allele length was determined in 634 people with PD and 422 healthy controls from an Australian cohort and the Parkinson's Progression Markers Initiative (PPMI) cohort, using polymerase chain reaction or whole genome sequencing analysis. Genotype and allele frequencies of TOMM40 '523' and APOE ε did not differ significantly between the cohorts. Analyses revealed TOMM40 '523' allele groups were not associated with disease risk, while considering APOE ε genotype. Regression analyses revealed the TOMM40 S/S genotype was associated with a significantly later age of symptom onset in the PPMI PD cohort, but not after correction for covariates, or in the Australian cohort. Whilst variation in the TOMM40 '523' polymorphism was not associated with PD risk, the possibility that it may be a modifying factor for age of symptom onset warrants further investigation in other PD populations.
线粒体功能异常是帕金森病（PD）发病机制中的一个关键过程。线粒体的中央孔形成蛋白 TOM40 由外膜转位酶 40 同源物基因（TOMM40）编码。高度变异的“523”多聚 T 重复与阿尔茨海默病相关的认知能力下降和发病年龄有关，但它是否在改变 PD 的风险或临床病程中起作用仍有待阐明。在来自澳大利亚队列和帕金森病进展标志物倡议（PPMI）队列的 634 名 PD 患者和 422 名健康对照者中，使用聚合酶链反应或全基因组测序分析确定了 TOMM40“523”等位基因长度。TOMM40“523”和 APOE ε 的基因型和等位基因频率在两个队列之间没有显著差异。分析表明，TOMM40“523”等位基因组与疾病风险无关，而考虑 APOE ε 基因型时则无关。回归分析显示，在 PPMI PD 队列中，TOMM40 S/S 基因型与症状出现年龄明显延迟相关，但在考虑协变量后或在澳大利亚队列中则无相关性。虽然 TOMM40“523”多态性的变化与 PD 风险无关，但它可能是症状出现年龄的修饰因素，值得在其他 PD 人群中进一步研究。
