title: Reduced protein stability of human DJ-1/PARK7 L166P, linked to autosomal recessive Parkinson disease, is due to direct endoproteolytic cleavage by the proteasome.
abstract: Parkinson's disease (PD) is characterized by dopaminergic dysfunction and degeneration. DJ-1/PARK7 mutations have been linked with a familial form of early onset PD. In this study, we found that human DJ-1 wild type and the missense mutants M26I, R98Q, A104T and D149A were stable proteins in cells, only the L166P mutant was unstable. In parallel, the former were not degraded and the L166P mutant was directly degraded in vitro by proteasome-mediated endoproteolytic cleavage. Furthermore, genetic evidence in fission yeast showed the direct involvement of proteasome in the degradation of human DJ-1 L166P and the corresponding L169P mutant of SPAC22E12.03c, the human orthologue of DJ-1 in Schizosaccharomyces Pombe, as their protein levels were increased at restrictive temperature in fission yeast (mts4 and pts1-732) harboring temperature sensitive mutations in proteasomal subunits. In total, our results provide evidence that direct proteasomal endoproteolytic cleavage of DJ-1 L166P is the mechanism of degradation contributing to the loss-of-function of the mutant protein, a property not shared by other DJ-1 missense mutants associated with PD.
authors.affiliation: Departamento de Bioquímica, Instituto de Investigaciones Biomédicas Alberto Sols, UAM-CSIC, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Alvarez-Castelao
authors.forename: Carolina
authors.initials: C
authors.lastname: Muñoz
authors.forename: Isabel
authors.initials: I
authors.lastname: Sánchez
authors.forename: Marc
authors.initials: M
authors.lastname: Goethals
authors.forename: Joël
authors.initials: J
authors.lastname: Vandekerckhove
authors.forename: José G
authors.initials: JG
authors.lastname: Castaño
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D015513:Oncogene Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism*; D000071617:Protein Deglycase DJ-1; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D012568:Schizosaccharomyces / Q000235:genetics / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D010455:Peptides; D021122:Protein Subunits; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D046988:Proteasome Endopeptidase Complex