Loss of function of DJ-1 triggered by Parkinson's disease-associated mutation is due to proteolytic resistance to caspase-6.
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.
Giaime
E
E
Institut de Neuromédecine Moléculaire IN2M and Institut de Pharmacologie Moléculaire et Cellulaire, UMR6097 CNRS/UNSA, Equipe labellisée Fondation pour la Recherche Médicale, 06560, Sophia-Antipolis, Valbonne, France.
Sunyach
C
C
Druon
C
C
Scarzello
S
S
Robert
G
G
Grosso
S
S
Auberger
P
P
Goldberg
M S
MS
Shen
J
J
Heutink
P
P
Pouysségur
J
J
Pagès
G
G
Checler
F
F
Alves da Costa
C
C
D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism; D053178:Caspase 6 / Q000378:metabolism*; D002478:Cells, Cultured; D019281:Dimerization; D015536:Down-Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D000071617:Protein Deglycase DJ-1; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D053178:Caspase 6
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