title: Familial Mutations and Post-translational Modifications of UCH-L1 in Parkinson's Disease and Neurodegenerative Disorders.
abstract: 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.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, 128, Section 2, Academia Road, Taipei, 11529,Taiwan. China.
authors.forename: Yun-Tzai C
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, 128, Section 2, Academia Road, Aipei, 11529,Taiwan, China.
authors.forename: Shang-Te D
authors.initials: SD
authors.lastname: Hsu
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D018450:Disease Progression; D015870:Gene Expression; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism* / Q000648:ultrastructure; D008958:Models, Molecular; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000072417:Protein Domains; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary; D043222:Ubiquitin Thiolesterase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: C482860:UCHL1 protein, human; D051844:alpha-Synuclein; D043222:Ubiquitin Thiolesterase
keywords: Lewy bodies; Parkinson’s disease; UCH-L1; misfolding; ubiquitin; α-synuclein