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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.
AuthorsHee-Jung Kim, Hyun Jung Kim, Jae-Eun Jeong, Jeong Yeob Baek, Jaeho Jeong, Sun Kim, Young-Mee Kim, Youhwa Kim, Jin Han Nam, Sue Hee Huh, Jawon Seo, Byung Kwan Jin, Kong-Joo Lee
JournalPloS one (PLoS One) Vol. 9 Issue 6 Pg. e99654 ( 2014) ISSN: 1932-6203 [Electronic] United States
PMID24959670 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Ubiquitin carboxyl-Terminal Hydrolase L-1, human
  • Hydrogen Peroxide
  • Ubiquitin Thiolesterase
Topics
  • Animals
  • Brain (enzymology, pathology)
  • Cell Line, Tumor
  • Deuterium Exchange Measurement
  • Disease Models, Animal
  • Enzyme Stability
  • HeLa Cells
  • Humans
  • Hydrogen Peroxide (pharmacology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria (metabolism)
  • Parkinson Disease (genetics, pathology)
  • Protein Processing, Post-Translational
  • Ubiquitin Thiolesterase (chemistry, genetics, metabolism)

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