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Parkin-mediated ubiquitination regulates phospholipase C-γ1
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 fo...
Autores principales: | , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
John Wiley & Sons, Ltd
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2832102/ https://www.ncbi.nlm.nih.gov/pubmed/18671761 http://dx.doi.org/10.1111/j.1582-4934.2008.00443.x |
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author | Dehvari, Nodi Sandebring, Anna Flores-Morales, Amilcar Mateos, Laura Chuan, Yin-Choy Goldberg, Matthew S Cookson, Mark R Cowburn, Richard F Cedazo-Mínguez, Angel |
author_facet | Dehvari, Nodi Sandebring, Anna Flores-Morales, Amilcar Mateos, Laura Chuan, Yin-Choy Goldberg, Matthew S Cookson, Mark R Cowburn, Richard F Cedazo-Mínguez, Angel |
author_sort | Dehvari, Nodi |
collection | PubMed |
description | 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 PLCγ1 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 PLCγ1 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 PLCγ1 is significantly higher in parkin KO mice and lower in parkin WT human neuroblastoma cells, suggesting that parkin ubiquitination of PLCγ1 is required for proteasomal degradation. In line with this idea, we show that the ability to ubiquitinate PLCγ1 in vitro differs significantly between WT and familial mutant parkin. In this study, we demonstrate that parkin interacts with PLCγ1, affecting PLCγ1 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. |
format | Text |
id | pubmed-2832102 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | John Wiley & Sons, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-28321022010-09-01 Parkin-mediated ubiquitination regulates phospholipase C-γ1 Dehvari, Nodi Sandebring, Anna Flores-Morales, Amilcar Mateos, Laura Chuan, Yin-Choy Goldberg, Matthew S Cookson, Mark R Cowburn, Richard F Cedazo-Mínguez, Angel J Cell Mol Med Articles 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 PLCγ1 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 PLCγ1 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 PLCγ1 is significantly higher in parkin KO mice and lower in parkin WT human neuroblastoma cells, suggesting that parkin ubiquitination of PLCγ1 is required for proteasomal degradation. In line with this idea, we show that the ability to ubiquitinate PLCγ1 in vitro differs significantly between WT and familial mutant parkin. In this study, we demonstrate that parkin interacts with PLCγ1, affecting PLCγ1 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. John Wiley & Sons, Ltd 2009-09 2008-07-30 /pmc/articles/PMC2832102/ /pubmed/18671761 http://dx.doi.org/10.1111/j.1582-4934.2008.00443.x Text en © 2008 The Authors Journal compilation © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd |
spellingShingle | Articles Dehvari, Nodi Sandebring, Anna Flores-Morales, Amilcar Mateos, Laura Chuan, Yin-Choy Goldberg, Matthew S Cookson, Mark R Cowburn, Richard F Cedazo-Mínguez, Angel Parkin-mediated ubiquitination regulates phospholipase C-γ1 |
title | Parkin-mediated ubiquitination regulates phospholipase C-γ1 |
title_full | Parkin-mediated ubiquitination regulates phospholipase C-γ1 |
title_fullStr | Parkin-mediated ubiquitination regulates phospholipase C-γ1 |
title_full_unstemmed | Parkin-mediated ubiquitination regulates phospholipase C-γ1 |
title_short | Parkin-mediated ubiquitination regulates phospholipase C-γ1 |
title_sort | parkin-mediated ubiquitination regulates phospholipase c-γ1 |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2832102/ https://www.ncbi.nlm.nih.gov/pubmed/18671761 http://dx.doi.org/10.1111/j.1582-4934.2008.00443.x |
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