title: DJ-1 interactions with α-synuclein attenuate aggregation and cellular toxicity in models of Parkinson's disease.
abstract: Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by the loss of neurons in the substantia nigra pars compacta and the presence of Lewy bodies in surviving neurons. These intracellular protein inclusions are primarily composed of misfolded α-synuclein (aSyn), which has also been genetically linked to familial and sporadic forms of PD. DJ-1 is a small ubiquitously expressed protein implicated in several pathways associated with PD pathogenesis. Although mutations in the gene encoding DJ-1 lead to familial early-onset PD, the exact mechanisms responsible for its role in PD pathogenesis are still elusive. Previous work has found that DJ-1--which has protein chaperone-like activity--modulates aSyn aggregation. Here, we investigated possible physical interactions between aSyn and DJ-1 and any consequent functional and pathological relevance. We found that DJ-1 interacts directly with aSyn monomers and oligomers in vitro, and that this also occurs in living cells. Notably, several PD-causing mutations in DJ-1 constrain this interaction. In addition, we found that overexpression of DJ-1 reduces aSyn dimerization, whereas mutant forms of DJ-1 impair this process. Finally, we found that human DJ-1 as well as yeast orthologs of DJ-1 reversed aSyn-dependent cellular toxicity in Saccharomyces cerevisiae. Taken together, these data suggest that direct interactions between DJ-1 and aSyn constitute the basis for a neuroprotective mechanism and that familial mutations in DJ-1 may contribute to PD by disrupting these interactions.
authors: Department of NeuroDegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany.
authors: L
authors: L
authors: Zondler
authors: 1] Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal [2] Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.
authors: L
authors: L
authors: Miller-Fleming
authors: Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.
authors: M
authors: M
authors: Repici
authors: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors: S
authors: S
authors: Gonçalves
authors: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors: S
authors: S
authors: Tenreiro
authors: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors: R
authors: R
authors: Rosado-Ramos
authors: Danish Research Institute of Translational Neuroscience - Dandrite, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors: C
authors: C
authors: Betzer
authors: Centre for Core Biotechnology Services, University of Leicester, Leicester LE1 7RH, UK.
authors: K R
authors: KR
authors: Straatman
authors: Danish Research Institute of Translational Neuroscience - Dandrite, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors: P H
authors: PH
authors: Jensen
authors: Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.
authors: F
authors: F
authors: Giorgini
authors: 1] Department of NeuroDegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany [2] Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors: T F
authors: TF
authors: Outeiro
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism*; D066329:Protein Aggregates; D011485:Protein Binding; D000071617:Protein Deglycase DJ-1; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D066329:Protein Aggregates; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051844:alpha-Synuclein; D054464:Peroxiredoxins; C105131:PARK7 protein, human; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1