Parkin-mediated ubiquitination regulates phospholipase C-γ1
Autor: | Nodi Dehvari, Richard F. Cowburn, Yin-Choy Chuan, Amilcar Flores-Morales, Mark R. Cookson, Anna Sandebring, Matthew S. Goldberg, Angel Cedazo-Minguez, Laura Mateos |
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Jazyk: | angličtina |
Rok vydání: | 2008 |
Předmět: |
Male
Parkinson's disease Ubiquitin-Protein Ligases Mutant Parkin Gene Expression Regulation Enzymologic Mice Ubiquitin medicine Animals Humans parkin Aged Aged 80 and over Mice Knockout biology Phospholipase C Phospholipase C gamma Cell Biology Articles phospholipase Cγ1 medicine.disease Phenotype Molecular biology Ubiquitin ligase nervous system diseases Protein Structure Tertiary Cell culture Mutation biology.protein Parkinson’s disease Molecular Medicine |
Zdroj: | Journal of Cellular and Molecular Medicine |
ISSN: | 1582-4934 1582-1838 |
Popis: | Mutations in parkin cause autosomal recessive forms of Parkinson's disease (PD), with an early age of onset and similar pathological phenotype to the idiopathic disease. Parkin has been identified as an E3 ubiquitin ligase that mediates different types of ubiquitination, which has made the search for substrates an intriguing possibility to identify pathological mechanisms linked to PD. In this study, we present PLCgamma1 as a novel substrate for parkin. This association was found in non-transfected human neuroblastoma SH-SY5Y cells as well as in stable cell lines expressing parkin WT and familial mutants R42P and G328E. Analysis of cortical, striatal and nigral human brain homogenates revealed that the interaction between parkin and PLCgamma1 is consistent throughout these regions, suggesting that the interaction is likely to have a physiological relevance for humans. Unlike many of the previously identified substrates, we could also show that the steady-state levels of PLCgamma1 is significantly higher in parkin KO mice and lower in parkin WT human neuroblastoma cells, suggesting that parkin ubiquitination of PLCgamma1 is required for proteasomal degradation. In line with this idea, we show that the ability to ubiquitinate PLCgamma1 in vitro differs significantly between WT and familial mutant parkin. In this study, we demonstrate that parkin interacts with PLCgamma1, affecting PLCgamma1 steady state protein levels in human and murine models with manipulated parkin function and expression levels. This finding could be of relevance for finding novel pathogenic mechanisms leading to PD. |
Databáze: | OpenAIRE |
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