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DJ-1 interactions with α-synuclein attenuate aggregation and cellular toxicity in models of Parkinson's disease.

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posted on 30.03.2015, 11:00 by L. Zondler, L. Miller-Fleming, M. Repici, S. Gonçalves, S. Tenreiro, R. Rosado-Ramos, C. Betzer, K. R. Straatman, P. H. Jensen, F. Giorgini, T. F. Outeiro
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.

Funding

This work was supported by funding from Parkinson’s UK (Research Grant G-0902), Fundação Calouste Gulbenkian and by Fundação para a Ciência e Tecnologia project PTDC/BIA-BCM/117975/2010, and fellowships SFRH/BPD/35767/2007 (ST), SFRH/BD/36065/2007 (LMF), SFRH/BD/79337/2011 (SG) and IMM/BTI/91-2012 (RRR). TFO was also supported by an EMBO Installation Grant and by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB).

History

Citation

Cell Death and Disease, 2014, 5, pp. e1350-?

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Biological Sciences/Department of Biochemistry

Version

VoR (Version of Record)

Published in

Cell Death and Disease

Publisher

Nature Publishing Group for Associazione Differenziamento e Morte Cellulare

issn

2041-4889

eissn

2041-4889

Available date

30/03/2015

Publisher version

http://www.nature.com/cddis/journal/v5/n7/full/cddis2014307a.html

Notes

PMCID: PMC4123098

Language

en

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