Lee Yun-Tzai C, Hsu Shang-Te D
Institute of Biological Chemistry, Academia Sinica, 128, Section 2, Academia Road, Taipei, 11529,Taiwan. China.
Institute of Biological Chemistry, Academia Sinica, 128, Section 2, Academia Road, Aipei, 11529,Taiwan, China.
Curr Protein Pept Sci. 2017;18(7):733-745. doi: 10.2174/1389203717666160217143721.
Parkinson's disease (PD) is one of the most common progressive neurodegenerative disorders in modern society. The disease involves many genetic risk factors as well as a sporadic pathogenesis that is age- and environment-dependent. Of particular interest is the formation of intra-neural fibrillar aggregates, namely Lewy bodies (LBs), the histological hallmark of PD, which results from aberrant protein homeostasis or misfolding that results in neurotoxicity. A better understanding of the molecular mechanism and composition of these cellular inclusions will help shed light on the progression of misfolding-associated neurodegenerative disorders. Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is found to co-aggregate with α-synuclein (αS), the major component of LBs. Several familial mutations of UCH-L1, namely p.Ile93Met (p.I93M), p.Glu7Ala (p.E7A), and p.Ser18Tyr (p.S18Y), are associated with PD and other neurodegenerative disorders. Here, we review recent progress and recapitulate the impact of PD-associated mutations of UCH-L1 in the context of their biological functions gleaned from biochemical and biophysical studies. Finally, we summarize the effect of these genetic mutations and post-translational modifications on the association of UCHL1 and PD in terms of loss of cellular functions or gain of cellular toxicity.
帕金森病（PD）是现代社会中最常见的进行性神经退行性疾病之一。该疾病涉及许多遗传风险因素以及与年龄和环境相关的散发性发病机制。特别值得关注的是神经内纤维状聚集体的形成，即路易小体（LBs），它是PD的组织学标志，由异常的蛋白质稳态或错误折叠导致神经毒性引起。更好地理解这些细胞内含物的分子机制和组成将有助于揭示与错误折叠相关的神经退行性疾病的进展。泛素羧基末端水解酶L1（UCH-L1）被发现与路易小体的主要成分α-突触核蛋白（αS）共同聚集。UCH-L1的几种家族性突变，即p.Ile93Met（p.I93M）、p.Glu7Ala（p.E7A）和p.Ser18Tyr（p.S18Y），与PD和其他神经退行性疾病有关。在这里，我们回顾了最近的进展，并根据从生化和生物物理研究中收集到的生物学功能，概括了UCH-L1的PD相关突变的影响。最后，我们从细胞功能丧失或细胞毒性增加的角度总结了这些基因突变和翻译后修饰对UCHL1与PD关联的影响。
