Journal
CELL DEATH AND DIFFERENTIATION
Volume 17, Issue 1, Pages 158-169Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2009.116
Keywords
Parkinson's diseased; DJ1; p53; caspase 6; autosomal recessive cases; mutations
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Funding
- Fondation pour la recherche medicale
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [P50NS038375] Funding Source: NIH RePORTER
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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 (2010) 17, 158-169; doi:10.1038/cdd.2009.116; published online 14 August 2009
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