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DJ-1 interactions with α-synuclein attenuate aggregation and cellular toxicity in models of Parkinson's disease.
Cell Death Dis. 2014 Jul 24; 5:e1350.CD

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+Show Affiliations

Department of NeuroDegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany.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.Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.Danish Research Institute of Translational Neuroscience - Dandrite, Department of Biomedicine, Aarhus University, Aarhus, Denmark.Centre for Core Biotechnology Services, University of Leicester, Leicester LE1 7RH, UK.Danish Research Institute of Translational Neuroscience - Dandrite, Department of Biomedicine, Aarhus University, Aarhus, Denmark.Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25058424

Citation

Zondler, L, et al. "DJ-1 Interactions With Α-synuclein Attenuate Aggregation and Cellular Toxicity in Models of Parkinson's Disease." Cell Death & Disease, vol. 5, 2014, pp. e1350.
Zondler L, Miller-Fleming L, Repici M, et al. DJ-1 interactions with α-synuclein attenuate aggregation and cellular toxicity in models of Parkinson's disease. Cell Death Dis. 2014;5:e1350.
Zondler, L., Miller-Fleming, L., Repici, M., Gonçalves, S., Tenreiro, S., Rosado-Ramos, R., Betzer, C., Straatman, K. R., Jensen, P. H., Giorgini, F., & Outeiro, T. F. (2014). DJ-1 interactions with α-synuclein attenuate aggregation and cellular toxicity in models of Parkinson's disease. Cell Death & Disease, 5, e1350. https://doi.org/10.1038/cddis.2014.307
Zondler L, et al. DJ-1 Interactions With Α-synuclein Attenuate Aggregation and Cellular Toxicity in Models of Parkinson's Disease. Cell Death Dis. 2014 Jul 24;5:e1350. PubMed PMID: 25058424.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - DJ-1 interactions with α-synuclein attenuate aggregation and cellular toxicity in models of Parkinson's disease. AU - Zondler,L, AU - Miller-Fleming,L, AU - Repici,M, AU - Gonçalves,S, AU - Tenreiro,S, AU - Rosado-Ramos,R, AU - Betzer,C, AU - Straatman,K R, AU - Jensen,P H, AU - Giorgini,F, AU - Outeiro,T F, Y1 - 2014/07/24/ PY - 2014/03/13/received PY - 2014/06/11/revised PY - 2014/06/13/accepted PY - 2014/7/25/entrez PY - 2014/7/25/pubmed PY - 2015/6/5/medline SP - e1350 EP - e1350 JF - Cell death & disease JO - Cell Death Dis VL - 5 N2 - 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. SN - 2041-4889 UR - https://www.unboundmedicine.com/medline/citation/25058424/DJ_1_interactions_with_α_synuclein_attenuate_aggregation_and_cellular_toxicity_in_models_of_Parkinson's_disease_ L2 - https://doi.org/10.1038/cddis.2014.307 DB - PRIME DP - Unbound Medicine ER -