Mechanisms of VPS35-Mediated Neurodegeneration in Parkinson's Disease.
Mechanisms of VPS35-Mediated Neurodegeneration in Parkinson's Disease.
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DOI：
10.1016/bs.irmvd.2021.08.005
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Moore, Darren J
中科院分区：
文献类型：
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作者：
Sargent, Dorian;Moore, Darren J
帕金森病是一种散发性和常见的神经退行性运动障碍，由遗传风险、衰老和环境暴露之间的复杂相互作用引起。家族性PD占病例的约10%，并且已知由至少15个基因的突变遗传引起。空泡蛋白分选35直系同源物（VPS 35）基因突变导致迟发性常染色体显性遗传家族性PD。VPS 35是五聚体逆转录复合物的关键亚单位，其在跨膜货物蛋白从内体到质膜和trans-Golgi网络的逆行分选和再循环中起作用。VPS 35中的单个杂合Asp 620 Asn（D 620 N）突变已在与PD分离的多个家族中被鉴定，并且已经开发了许多实验细胞和动物模型以了解其致病作用。在分子水平上，D 620 N突变已被证明会损害VPS 35与WASH复合物的相互作用，WASH复合物在依赖于逆转录酶的分选中起辅助作用。此外，D 620 N突变与逆转录病毒货物的异常分选有关，包括CI-M6 PR，AMPA受体亚基，MUL 1，LAMP 2a和ATG 9A，以及LRRK 2超活化。在细胞水平，数据支持D 620 N VPS 35通过改变的内体分选对线粒体功能、自噬-溶酶体途径、Wnt信号传导和神经传递的影响。在啮齿动物模型中，异常逆转录分子分选和细胞途径与D 620 N VPS 35诱导的PD相关神经退行性表型的相关性尚不清楚。关于D 620 N突变的作用机制以及它是否通过功能获得和/或部分显性负性机制在动物模型和PD中表现出致病作用也存在不确定性。在这里，我们讨论了新兴的分子和细胞机制的基础上引起的PD家族VPS 35突变，从结构到细胞功能的神经病理学。我们进一步讨论了与其他神经退行性疾病和潜在的治疗策略，以恢复正常的retromer功能，以减轻疾病的功能减少retromer的研究。
Parkinson’s disease is a sporadic and common neurodegenerative movement disorder resulting from the complex interplay between genetic risk, aging and environmental exposure. Familial forms of PD account for ~10% of cases and are known to result from the inheritance of mutations in at least 15 genes. Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene cause late-onset, autosomal dominant familial PD. VPS35 is a key suunit of the pentameric retromer complex that plays a role in the retrograde sorting and recycling of transmembrane cargo proteins from endosomes to the plasma membrane and trans-Golgi network. A single heterozygous Asp620Asn (D620N) mutation in VPS35 has been identified in multiple families that segregates with PD, and a number of experimental cellular and animal models have been developed to understand its pathogenic effects. At the molecular level, the D620N mutation has been shown to impair the interaction of VPS35 with the WASH complex, that plays an accessory function in retromer-dependent sorting. In addition, the D620N mutation has been linked to the abnormal sorting of retromer cargo, including CI-M6PR, AMPA receptor subunits, MUL1, LAMP2a and ATG9A, as well as to LRRK2 hyperactivation. At the cellular level, data support an impact of D620N VPS35 on mitochondrial function, the autophagy-lysosomal pathway, Wnt signaling and neurotransmission via altered endosomal sorting. The relevance of abnormal retromer sorting and cellular pathways to PD-related neurodegenerative phenotypes induced by D620N VPS35 in rodent models is not yet clear. There is also uncertainty regarding the mechanism-of-action of the D620N mutation and whether it manifests pathogenic effects in animal models and PD through a gain-of-function and/or a partial dominant-negative mechanism. Here, we discuss the emerging molecular and cellular mechanisms underlying PD induced by familial VPS35 mutations, going from structure to cellular function to neuropathology. We further discuss studies linking reduced retromer function to other neurodegenerative diseases and potential therapeutic strategies to normalize retromer function to mitigate disease.