title: N-terminal truncated UCH-L1 prevents Parkinson's disease associated damage.
abstract: Ubiquitin C-terminal hydrolase-L1 (UCH-L1) has been proposed as one of the Parkinson's disease (PD) related genes, but the possible molecular connection between UCH-L1 and PD is not well understood. In this study, we discovered an N-terminal 11 amino acid truncated variant UCH-L1 that we called NT-UCH-L1, in mouse brain tissue as well as in NCI-H157 lung cancer and SH-SY5Y neuroblastoma cell lines. In vivo experiments and hydrogen-deuterium exchange (HDX) with tandem mass spectrometry (MS) studies showed that NT-UCH-L1 is readily aggregated and degraded, and has more flexible structure than UCH-L1. Post-translational modifications including monoubiquitination and disulfide crosslinking regulate the stability and cellular localization of NT-UCH-L1, as confirmed by mutational and proteomic studies. Stable expression of NT-UCH-L1 decreases cellular ROS levels and protects cells from H2O2, rotenone and CCCP-induced cell death. NT-UCH-L1-expressing transgenic mice are less susceptible to degeneration of nigrostriatal dopaminergic neurons seen in the MPTP mouse model of PD, in comparison to control animals. These results suggest that NT-UCH-L1 may have the potential to prevent neural damage in diseases like PD.
authors: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors: Hee-Jung
authors: HJ
authors: Kim
authors: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors: Hyun Jung
authors: HJ
authors: Kim
authors: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors: Jae-Eun
authors: JE
authors: Jeong
authors: Department of Biochemistry and Molecular Biology, Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul, Korea.
authors: Jeong Yeob
authors: JY
authors: Baek
authors: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors: Jaeho
authors: J
authors: Jeong
authors: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors: Sun
authors: S
authors: Kim
authors: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors: Young-Mee
authors: YM
authors: Kim
authors: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors: Youhwa
authors: Y
authors: Kim
authors: Department of Biochemistry and Molecular Biology, Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul, Korea.
authors: Jin Han
authors: JH
authors: Nam
authors: Department of Biochemistry and Molecular Biology, Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul, Korea.
authors: Sue Hee
authors: SH
authors: Huh
authors: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors: Jawon
authors: J
authors: Seo
authors: Department of Biochemistry and Molecular Biology, Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul, Korea.
authors: Byung Kwan
authors: BK
authors: Jin
authors: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors: Kong-Joo
authors: KJ
authors: Lee
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D041961:Deuterium Exchange Measurement; D004195:Disease Models, Animal; D004795:Enzyme Stability; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology*; D011499:Protein Processing, Post-Translational; D043222:Ubiquitin Thiolesterase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: C507533:Ubiquitin carboxyl-Terminal Hydrolase L-1, human; D006861:Hydrogen Peroxide; D043222:Ubiquitin Thiolesterase