title: Loss of DJ-1 protein stability and cytoprotective function by Parkinson's disease-associated proline-158 deletion.
abstract: DJ-1 is a ubiquitous protein regulating cellular viability. Recessive mutations in the PARK7/DJ-1 gene are linked to Parkinson's disease (PD). Although the most dramatic L166P point mutation practically eliminates DJ-1 protein and function, the effects of other PD-linked mutations are subtler. Here, we investigated two recently described PD-associated DJ-1 point mutations, the A179T substitution and the P158Δ in-frame deletion. [A179T]DJ-1 protein was as stable as wild-type [wt]DJ-1, but the P158Δ mutant protein was less stable. In accord with the notion that dimer formation is essential for DJ-1 protein stability, [P158Δ]DJ-1 was impaired in dimer formation. Similar to our previous findings for [M26I]DJ-1, [P158Δ]DJ-1 bound aberrantly to apoptosis signal-regulating kinase 1. Thus, the PD-associated P158Δ mutation destabilizes DJ-1 protein and function. As there is also evidence for an involvement of DJ-1 in multiple system atrophy, a PD-related α-synucleinopathy characterized by oligodendroglial cytoplasmic inclusions, we studied an oligodendroglial cell line stably expressing α-synuclein. α-Synuclein aggregate dependent microtubule retraction upon co-transfection with tubulin polymerization-promoting protein p25α was ameliorated by [wt]DJ-1. In contrast, DJ-1 mutants including P158Δ failed to protect in this system, where we found evidence of apoptosis signal-regulating kinase 1 (ASK1) involvement. In conclusion, the P158Δ point mutation may contribute to neurodegeneration by protein destabilization and hence loss of DJ-1 function.
authors.affiliation: Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, Faculty of Medicine, University of Tübingen, Germany.
authors.forename: Emmy H
authors.initials: EH
authors.lastname: Rannikko
authors.affiliation: Department of Biomedicine, Faculty of Health Sciences, University of Aarhus, Denmark.|H. Lundbeck A/S, Department of Neurodegeneration, Valby, Denmark.
authors.forename: Louise Buur
authors.initials: LB
authors.lastname: Vesterager
authors.affiliation: Department of Biomedicine, Faculty of Health Sciences, University of Aarhus, Denmark.
authors.forename: Jafar H A
authors.initials: JH
authors.lastname: Shaik
authors.affiliation: Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, Faculty of Medicine, University of Tübingen, Germany.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Weber
authors.affiliation: Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, Faculty of Medicine, University of Tübingen, Germany.
authors.forename: Elena M
authors.initials: EM
authors.lastname: Cornejo Castro
authors.affiliation: H. Lundbeck A/S, Department of Neurodegeneration, Valby, Denmark.
authors.forename: Karina
authors.initials: K
authors.lastname: Fog
authors.affiliation: Department of Biomedicine, Faculty of Health Sciences, University of Aarhus, Denmark.
authors.forename: Poul H
authors.initials: PH
authors.lastname: Jensen
authors.affiliation: Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, Faculty of Medicine, University of Tübingen, Germany.|German Center for Neurodegenerative Diseases, Tübingen, Germany.
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Kahle
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D019578:Multiple System Atrophy / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D054464:Peroxiredoxins / Q000235:genetics; D017354:Point Mutation; D011392:Proline / Q000235:genetics; D000071617:Protein Deglycase DJ-1; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D051381:Rats; D014162:Transfection
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D011392:Proline; D054464:Peroxiredoxins; C105131:PARK7 protein, human; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1