VPS35, the Retromer Complex and Parkinson's Disease.
VPS35, the Retromer Complex and Parkinson's Disease.
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DOI：
10.3233/jpd-161020
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Moore DJ
中科院分区：
文献类型：
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作者：
Williams ET;Chen X;Moore DJ
编码逆转录复合物核心成分的液泡蛋白分选 35 直向同源基因 (VPS35) 基因的突变最近已成为迟发性常染色体显性家族性帕金森病 (PD) 的新病因。迄今为止，已明确确定一种错义突变 AspD620Asn (D620N) 可导致全球多个个人和家庭罹患帕金森病。 VPS35 突变诱导 PD 进行性神经变性的确切分子机制尚不清楚。了解这些机制以及突变型 VPS35 下游受干扰的细胞途径对于制定适当的治疗策略非常重要。在这篇综述中，我们重点关注当前有关 VPS35 的知识及其在 PD 中的作用。我们对从遗传细胞和动物模型中收集到的突变型 VPS35 介导的神经变性机制的新数据进行了批判性讨论，并重点介绍了最新进展，这些进展可能有助于深入了解 VPS35 与其他几种 PD 相关基因产物（即 α-突触核蛋白、LRRK2 和 Parkin）在 PD 中的相互作用。目前的数据支持 VPS35 和逆转录酶功能紊乱在 PD 发病机制中的作用。
Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene encoding a core component of the retromer complex, have recently emerged as a new cause of late-onset, autosomal dominant familial Parkinson’s disease (PD). A single missense mutation, AspD620Asn (D620N), has so far been unambiguously identified to cause PD in multiple individuals and families worldwide. The exact molecular mechanism(s) by which VPS35 mutations induce progressive neurodegeneration in PD are not yet known. Understanding these mechanisms, as well as the perturbed cellular pathways downstream of mutant VPS35, is important for the development of appropriate therapeutic strategies. In this review, we focus on the current knowledge surrounding VPS35 and its role in PD. We provide a critical discussion of the emerging data regarding the mechanisms underlying mutant VPS35-mediated neurodegeneration gleaned from genetic cell and animal models and highlight recent advances that may provide insight into the interplay between VPS35 and several other PD-linked gene products (i.e. α-synuclein, LRRK2 and parkin) in PD. Present data support a role for perturbed VPS35 and retromer function in the pathogenesis of PD.