Huang Xiurong, Wang Yige, Xiang Yaqin, Zhao Yuwen, Pan Hongxu, Liu Zhenhua, Xu Qian, Sun Qiying, Tan Jieqiong, Yan Xinxiang, Li Jinchen, Tang Beisha, Guo Jifeng
Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China.
CNS Neurosci Ther. 2024 Oct;30(10):e70070. doi: 10.1111/cns.70070.
Parkinson's disease (PD) is a neurodegenerative disease caused by a combination of aging, environmental, and genetic factors. Previous research has implicated both causative and susceptibility genes in PD development. Nogo-A, a neurite outgrowth inhibitor, has been shown to impact axon growth through ligand-receptor interactions negatively, thereby involved in the deterioration of dopaminergic neurons. However, rare genetic studies have identified the relationship between neurite outgrowth inhibitor (Nogo)-associated genes and PD from a signaling pathway perspective.
We enrolled 3959 PD patients and 2931 healthy controls, categorized into two cohorts based on their family history and age at onset: sporadic early Parkinson's disease & familial Parkinson's disease (sEOPD & FPD) cohort and sporadic late Parkinson's disease (sLOPD) cohort. We selected 17 Nogo-associated genes and stratified them into three groups via their function, respectively, ligand, receptors, and signaling pathway groups. Additionally, we conducted the burden analysis in rare variants, the logistic regression analysis in common variants, and the genotype-phenotype association analysis. Last, bioinformatics analysis and functional experiments were conducted to identify the role of the MTOR gene in PD.
Our findings demonstrated that the missense variants in the MTOR gene might increase PD risk, while the deleterious variants in the receptor subtype of Nogo-associated genes might mitigate PD risk. However, common variants of Nogo-associated genes showed no association with PD development in two cohorts. Furthermore, genotype-phenotype association analysis suggested that PD patients with MTOR gene variants exhibited relatively milder motor symptoms but were more susceptible developing dyskinesia. Additionally, bioinformatics analysis results showed MTOR gene was significantly decreased in PD, indicating a potential negative role of the mTOR in PD pathogenesis. Experimental data further demonstrated that MHY1485, a mTOR agonist, could rescue MPP-induced axon inhibition, further implicating the involvement of mTOR protein in PD by regulating cell growth and axon growth.
Our preliminary investigation highlights the association of Nogo-associated genes with PD onset in the Chinese mainland population and hints at the potential role of the MTOR gene in PD. Further research is warranted to elucidate the mechanistic pathways underlying these associations and their therapeutic implications.
帕金森病（PD）是一种由衰老、环境和遗传因素共同作用引起的神经退行性疾病。先前的研究表明，致病基因和易感基因均与PD的发生有关。轴突生长抑制因子Nogo-A已被证明可通过配体-受体相互作用对轴突生长产生负面影响，从而参与多巴胺能神经元的退化。然而，罕见的遗传学研究尚未从信号通路的角度确定轴突生长抑制因子（Nogo）相关基因与PD之间的关系。
我们招募了3959例PD患者和2931例健康对照，根据家族史和发病年龄将其分为两个队列：散发性早发型帕金森病和家族性帕金森病（sEOPD&FPD）队列以及散发性晚发型帕金森病（sLOPD）队列。我们选择了17个与Nogo相关的基因，并根据其功能将它们分别分为三组，即配体组、受体组和信号通路组。此外，我们对罕见变异进行了负荷分析，对常见变异进行了逻辑回归分析，并进行了基因型-表型关联分析。最后，进行了生物信息学分析和功能实验，以确定MTOR基因在PD中的作用。
我们的研究结果表明，MTOR基因中的错义变异可能会增加PD风险，而Nogo相关基因受体亚型中的有害变异可能会降低PD风险。然而，在两个队列中，Nogo相关基因的常见变异与PD的发生无关。此外，基因型-表型关联分析表明，携带MTOR基因变异的PD患者运动症状相对较轻，但更容易发生运动障碍。此外，生物信息学分析结果显示，PD患者的MTOR基因显著降低，表明mTOR在PD发病机制中可能具有潜在的负面作用。实验数据进一步表明，mTOR激动剂MHY1485可以挽救MPP诱导的轴突抑制，进一步表明mTOR蛋白通过调节细胞生长和轴突生长参与PD的发生。
我们的初步研究突出了Nogo相关基因与中国大陆人群PD发病之间的关联，并提示了MTOR基因在PD中的潜在作用。有必要进行进一步的研究，以阐明这些关联背后的机制途径及其治疗意义。
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