Loss of function of DJ-1 triggered by Parkinson's disease-associated mutation is due to proteolytic resistance to caspase-6
| Autor: | Gilles Pagès, Frédéric Checler, Peter Heutink, Jie Shen, Sabine Scarzello, Matthew S. Goldberg, Charlotte Druon, Guillaume Robert, Patrick Auberger, Sébastien Grosso, Emilie Giaime, Jacques Pouysségur, C. Alves da Costa, Claire Sunyach |
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| Přispěvatelé: | Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Centre méditérannéen de médecine moléculaire (C3M), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Neurologic Diseases, Brigham and Women's Hospital [Boston], Departments of Neurology and Psychiatry, University of Texas Southwestern Medical Center [Dallas], Section Medical Genomics, Department of Clinical Genetics, VU University Medical Center [Amsterdam], Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Human genetics, NCA - Neurodegeneration |
| Rok vydání: | 2010 |
| Předmět: |
p53
Parkinson's disease Proteolysis Protein Deglycase DJ-1 Down-Regulation Mutagenesis (molecular biology technique) Apoptosis Caspase 6 [SDV.BC]Life Sciences [q-bio]/Cellular Biology Biology medicine.disease_cause Article Mice 03 medical and health sciences caspase 6 0302 clinical medicine Parkinson's diseased medicine Animals Humans Molecular Biology Cells Cultured Loss function 030304 developmental biology Oncogene Proteins 0303 health sciences Mutation medicine.diagnostic_test DJ1 Intracellular Signaling Peptides and Proteins Brain Parkinson Disease Cell Biology medicine.disease mutations Phenotype Molecular biology 3. Good health Cell biology Amino Acid Substitution Mutagenesis Site-Directed [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Tumor Suppressor Protein p53 Dimerization 030217 neurology & neurosurgery autosomal recessive cases |
| Zdroj: | Cell Death and Differentiation Cell Death and Differentiation, Nature Publishing Group, 2009, epub ahead of print. ⟨10.1038/cdd.2009.116⟩ Cell Death and Differentiation, 17(1), 158-169. Nature Publishing Group Giaime, E, Sunyach, C, Druon, C, Scarzello, S, Robert, G, Grosso, S, Auberger, P, Goldberg, M S, Shen, J, Heutink, P, Pouyssegur, J, Pages, G, Checler, F & da Costa, C A 2010, ' Loss of function of DJ-1 triggered by Parkinson's disease-associated mutation is due to proteolytic resistance to caspase-6 ', Cell Death and Differentiation, vol. 17, no. 1, pp. 158-169 . https://doi.org/10.1038/cdd.2009.116 |
| ISSN: | 1350-9047 1476-5403 |
| Popis: | International audience; DJ-1 was recently identified as a gene product responsible for a subset of familial Parkinson's disease (PD). The mechanisms by which mutations in DJ-1 alter its function and account for PD-related pathology remained largely unknown. We show that DJ-1 is processed by caspase-6 and that the caspase-6-derived C-terminal fragment of DJ-1 fully accounts for associated p53-dependent cell death. In line with the above data, we show that a recently described early-onset PD-associated mutation (D149A) renders DJ-1 resistant to caspase-6 proteolysis and abolishes its protective phenotype. Unlike the D149A mutation, the L166P mutation that prevents DJ-1 dimerization does not impair its proteolysis by caspase-6 although it also abolishes DJ-1 antiapoptotic function. Therefore, we show here that DJ-1 loss of function could be due to impaired caspase-6 proteolysis and we document the fact that various DJ-1 mutations could lead to PD pathology through distinct molecular mechanisms.Cell Death and Differentiation advance online publication, 14 August 2009; doi:10.1038/cdd.2009.116. |
| Databáze: | OpenAIRE |
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