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The interplay of aging, genetics and environmental factors in the pathogenesis of Parkinson’s disease
Translational Neurodegeneration ( IF 10.8 ) Pub Date : 2019-08-16 , DOI: 10.1186/s40035-019-0165-9
Shirley Yin-Yu Pang 1 , Philip Wing-Lok Ho 1 , Hui-Fang Liu 1 , Chi-Ting Leung 1 , Lingfei Li 1 , Eunice Eun Seo Chang 1 , David Boyer Ramsden 2 , Shu-Leong Ho 1
Affiliation  

Parkinson’s disease (PD) is characterized by dopaminergic neuronal loss in the substantia nigra pars compacta and intracellular inclusions called Lewy bodies (LB). During the course of disease, misfolded α-synuclein, the major constituent of LB, spreads to different regions of the brain in a prion-like fashion, giving rise to successive non-motor and motor symptoms. Etiology is likely multifactorial, and involves interplay among aging, genetic susceptibility and environmental factors. The prevalence of PD rises exponentially with age, and aging is associated with impairment of cellular pathways which increases susceptibility of dopaminergic neurons to cell death. However, the majority of those over the age of 80 do not have PD, thus other factors in addition to aging are needed to cause disease. Discovery of neurotoxins which can result in parkinsonism led to efforts in identifying environmental factors which may influence PD risk. Nevertheless, the causality of most environmental factors is not conclusively established, and alternative explanations such as reverse causality and recall bias cannot be excluded. The lack of geographic clusters and conjugal cases also go against environmental toxins as a major cause of PD. Rare mutations as well as common variants in genes such as SNCA, LRRK2 and GBA are associated with risk of PD, but Mendelian causes collectively only account for 5% of PD and common polymorphisms are associated with small increase in PD risk. Heritability of PD has been estimated to be around 30%. Thus, aging, genetics and environmental factors each alone is rarely sufficient to cause PD for most patients. PD is a multifactorial disorder involving interplay of aging, genetics and environmental factors. This has implications on the development of appropriate animal models of PD which take all these factors into account. Common converging pathways likely include mitochondrial dysfunction, impaired autophagy, oxidative stress and neuroinflammation, which are associated with the accumulation and spread of misfolded α-synuclein and neurodegeneration. Understanding the mechanisms involved in the initiation and progression of PD may lead to potential therapeutic targets to prevent PD or modify its course.

中文翻译:

衰老、遗传和环境因素在帕金森病发病机制中的相互作用

帕金森病 (PD) 的特征是黑质致密部多巴胺能神经元丢失和称为路易体 (LB) 的细胞内包涵体。在疾病过程中,错误折叠的 α-突触核蛋白(LB 的主要成分)以类似朊病毒的方式扩散到大脑的不同区域,引起连续的非运动和运动症状。病因可能是多因素的,涉及衰老、遗传易感性和环境因素之间的相互作用。PD 的患病率随着年龄的增长而呈指数级上升,而衰老与细胞通路的损伤有关,从而增加了多巴胺能神经元对细胞死亡的敏感性。然而,大多数80岁以上的人并没有患PD,因此除了衰老之外还需要其他因素才能致病。可导致帕金森病的神经毒素的发现促使人们努力确定可能影响帕金森病风险的环境因素。然而,大多数环境因素的因果关系尚未最终确定,并且不能排除诸如反向因果关系和回忆偏差等替代解释。缺乏地理集群和夫妻病例也不利于环境毒素作为帕金森病的主要原因。SNCA、LRRK2 和 GBA 等基因的罕见突变和常见变异与 PD 风险相关,但孟德尔原因总共仅占 PD 的 5%,常见多态性与 PD 风险小幅增加相关。PD 的遗传率估计约为 30%。因此,对于大多数患者来说,衰老、遗传和环境因素本身不足以导致帕金森病。PD 是一种多因素疾病,涉及衰老、遗传和环境因素的相互作用。这对考虑所有这些因素的适当 PD 动物模型的开发具有影响。常见的聚合途径可能包括线粒体功能障碍、自噬受损、氧化应激和神经炎症,这些都与错误折叠的 α-突触核蛋白的积累和扩散以及神经变性有关。了解帕金森病发生和进展的机制可能会找到预防帕金森病或改变其病程的潜在治疗靶点。
更新日期:2020-04-22
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