Ubiquitin specific protease-13 independently regulates parkin ubiquitination and alpha-synuclein clearance in alpha-synucleinopathies.
Hum Mol Genet
; 28(4): 548-560, 2019 02 15.
Article
em En
| MEDLINE
| ID: mdl-30329047
ABSTRACT
Ubiquitin 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
/
Endopeptidases
/
Ubiquitina-Proteína Ligases
/
Alfa-Sinucleína
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article