• Xiaoguang Liu, Michaeline Hebron, Wangke Shi, Irina Lonskaya, and Charbel E-H Moussa.
• Department of Neurology, Laboratory for Dementia and Parkinsonism, Translational Neurotherapeutics Program, National Parkinson's Foundation Center of Excellence, Lewy Body Dementia Research Center of Excellence, Georgetown University Medical Center, N.W. Washington D.C., USA.
• Hum. Mol. Genet. 2019 Feb 15; 28 (4): 548-560.

AbstractUbiquitin specific proteases (USPs) are de-ubiquitinases (DUBs) that control protein ubiquitination cycle. The role of DUBs is poorly understood in neurodegenerative diseases. We found that USP13 is overexpressed in post-mortem Parkinson's disease (PD) brains. We investigated whether changes in USP13 levels can affect two molecules, parkin and alpha-synuclein, that are implicated in PD pathogenesis. Parkin is an E3 ubiquitin ligase that is regulated by ubiquitination and targets certain proteins for degradation, and alpha-synuclein may be ubiquitinated and recycled in the normal brain. We found that USP13 independently regulates parkin and alpha-synuclein ubiquitination in models of alpha-synucleinopathies. USP13 shRNA knockdown increases alpha-synuclein ubiquitination and clearance, in a parkin-independent manner. Furthermore, USP13 overexpression counteracts the effects of a tyrosine kinase inhibitor, Nilotinib, while USP13 knockdown facilitates Nilotinib effects on alpha-synculein clearance, suggesting that alpha-synuclein ubiquitnation is important for its clearance. These studies provide novel evidence of USP13 effects on parkin and alpha-synuclein metabolism and suggest that USP13 is a potential therapeutic target in the alpha-synucleinopathies.

28 keywords...

hide…