Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/31942
Title: DJ-1 interactions with α-synuclein attenuate aggregation and cellular toxicity in models of Parkinson's disease.
Authors: 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.
First Published: 24-Jul-2014
Publisher: Nature Publishing Group for Associazione Differenziamento e Morte Cellulare
Citation: Cell Death and Disease, 2014, 5, pp. e1350-?
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.
DOI Link: 10.1038/cddis.2014.307
ISSN: 2041-4889
eISSN: 2041-4889
Links: http://www.nature.com/cddis/journal/v5/n7/full/cddis2014307a.html
http://hdl.handle.net/2381/31942
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Creative Commons Attribution 3.0 Unported (CC BY 3.0) http://creativecommons.org/licenses/by/3.0/
Description: PMCID: PMC4123098
Appears in Collections:Published Articles, Dept. of Biochemistry

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