title: Versatile members of the DNAJ family show Hsp70 dependent anti-aggregation activity on RING1 mutant parkin C289G.
abstract: Parkinson's disease is one of the most common neurodegenerative disorders and several mutations in different genes have been identified to contribute to the disease. A loss of function parkin RING1 domain mutant (C289G) is associated with autosomal-recessive juvenile-onset Parkinsonism (AR-JP) and displays altered solubility and sequesters into aggregates. Single overexpression of almost each individual member of the Hsp40 (DNAJ) family of chaperones efficiently reduces parkin C289G aggregation and requires interaction with and activity of endogenously expressed Hsp70 s. For DNAJB6 and DNAJB8, potent suppressors of aggregation of polyglutamine proteins for which they rely mainly on an S/T-rich region, it was found that the S/T-rich region was dispensable for suppression of parkin C289G aggregation. Our data implies that different disease-causing proteins pose different challenges to the protein homeostasis system and that DNAJB6 and DNAJB8 are highly versatile members of the DNAJ protein family with multiple partially non-overlapping modes of action with respect to handling disease-causing proteins, making them interesting potential therapeutic targets.
authors.affiliation: University Medical Center Groningen, University of Groningen, Department of Cell Biology, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: Vaishali
authors.initials: V
authors.lastname: Kakkar
authors.affiliation: University Medical Center Groningen, University of Groningen, Department of Cell Biology, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.|European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: E F Elsiena
authors.initials: EF
authors.lastname: Kuiper
authors.affiliation: Utrecht University, Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Padualaan 8, 3584 CH, Utrecht, The Netherlands.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Pandey
authors.affiliation: Utrecht University, Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Padualaan 8, 3584 CH, Utrecht, The Netherlands.
authors.forename: Ineke
authors.initials: I
authors.lastname: Braakman
authors.affiliation: University Medical Center Groningen, University of Groningen, Department of Cell Biology, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: Harm H
authors.initials: HH
authors.lastname: Kampinga
mesh_terms: D019943:Amino Acid Substitution; D057809:HEK293 Cells; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics; D000072417:Protein Domains; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: C107481:DNAJA1 protein, human; C121958:DNAJB2 protein, human; C485565:DNAJB6 protein, human; C582953:DNAJB8 protein, human; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein