Nishioka Kenya, Imai Yuzuru, Yoshino Hiroyo, Li Yuanzhe, Funayama Manabu, Hattori Nobutaka
Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Front Neurol. 2022 Jun 2;13:764917. doi: 10.3389/fneur.2022.764917. eCollection 2022.
Over the past 20 years, numerous robust analyses have identified over 20 genes related to familial Parkinson's disease (PD), thereby uncovering its molecular underpinnings and giving rise to more sophisticated approaches to investigate its pathogenesis. α-Synuclein is a major component of Lewy bodies (LBs) and behaves in a prion-like manner. The discovery of α-Synuclein enables an in-depth understanding of the pathology behind the generation of LBs and dopaminergic neuronal loss. Understanding the pathophysiological roles of genes identified from PD families is uncovering the molecular mechanisms, such as defects in dopamine biosynthesis and metabolism, excessive oxidative stress, dysfunction of mitochondrial maintenance, and abnormalities in the autophagy-lysosome pathway, involved in PD pathogenesis. This review summarizes the current knowledge on familial PD genes detected by both single-gene analyses obeying the Mendelian inheritance and meta-analyses of genome-wide association studies (GWAS) from genome libraries of PD. Studying the functional role of these genes might potentially elucidate the pathological mechanisms underlying familial PD and sporadic PD and stimulate future investigations to decipher the common pathways between the diseases.
在过去20年里，大量有力的分析已鉴定出20多个与家族性帕金森病（PD）相关的基因，从而揭示了其分子基础，并催生了更复杂的方法来研究其发病机制。α-突触核蛋白是路易小体（LBs）的主要成分，其行为类似朊病毒。α-突触核蛋白的发现使人们能够深入了解路易小体形成和多巴胺能神经元丢失背后的病理机制。了解从帕金森病家族中鉴定出的基因的病理生理作用，正在揭示参与帕金森病发病机制的分子机制，如多巴胺生物合成和代谢缺陷、过度氧化应激、线粒体维持功能障碍以及自噬-溶酶体途径异常。本综述总结了通过遵循孟德尔遗传的单基因分析以及对帕金森病基因组文库进行全基因组关联研究（GWAS）的荟萃分析所检测到的家族性帕金森病基因的现有知识。研究这些基因的功能作用可能有助于阐明家族性帕金森病和散发性帕金森病的病理机制，并推动未来的研究以破译这两种疾病之间的共同途径。
