N-terminal truncated UCH-L1 prevents Parkinson's disease associated damage

Hee 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

Research output: Contribution to journalArticle

14 Scopus citations

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 H2O 2, 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.

Original languageEnglish (US)
Article numbere99654
JournalPloS one
Volume9
Issue number6
DOIs
StatePublished - Jun 24 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Kim, H. J., Kim, H. J., Jeong, J. E., Baek, J. Y., Jeong, J., Kim, S., Kim, Y-M., Kim, Y., Nam, J. H., Huh, S. H., Seo, J., Jin, B. K., & Lee, K. J. (2014). N-terminal truncated UCH-L1 prevents Parkinson's disease associated damage. PloS one, 9(6), [e99654]. https://doi.org/10.1371/journal.pone.0099654