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. © 2010 Macmillan Publishers Limited All rights reserved.
CITATION STYLE
Giaime, E., Sunyach, C., Druon, C., Scarzello, S., Robert, G., Grosso, S., … 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, 17(1), 158–169. https://doi.org/10.1038/cdd.2009.116
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