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Parkinson's disease-associated mutations in DJ-1 modulate its dimerization in living cells

Lookup NU author(s): Professor Tiago Outeiro

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Abstract

Mutations in the protein DJ-1 cause recessive forms of early onset familial Parkinson's disease (PD). To date, most of the causative mutations studied destabilize formation of DJ-1 homodimers, which appears to be closely linked to its normal function in oxidative stress and other cellular processes. Despite the importance of understanding the dimerization dynamics of this protein, this aspect of DJ-1 biology has not previously been directly studied in living cells. Here, we use bimolecular fluorescence complementation to study DJ-1 dimerization and find not only that DJ-1 forms homodimers in living cells but that most PD causative DJ-1 mutations disrupt this process, including the L166P, M26I, L10P, and P158â̂† mutations. Interestingly, the E64D mutant form of DJ-1 retains the ability to form homodimers. However, while wild-type DJ-1 dimers are stabilized under oxidative stress conditions, we find that the E64D mutation blocks this stabilization. Furthermore, our data show that the E64D mutation potentiates the formation of aggresomes containing DJ-1. We also observe that while the widely studied L166P mutation prevents DJ-1 from forming homodimers or heterodimers with wild-type protein, the mutant protein is able to partially disrupt formation of wild-type homodimers. In summary, by investigating DJ-1 dimerization in living cells, we have uncovered several novel properties of PD causative mutations in DJ-1, which may ultimately provide novel insight into PD pathogenesis and possible therapeutic options. © 2012 The Author(s).


Publication metadata

Author(s): Repici M, Straatman KR, Balduccio N, Enguita FJ, Outeiro TF, Giorgini F

Publication type: Article

Publication status: Published

Journal: Journal of Molecular Medicine

Year: 2013

Volume: 91

Issue: 5

Pages: 599-611

Print publication date: 01/05/2013

Online publication date: 27/11/2012

ISSN (print): 0946-2716

ISSN (electronic): 1432-1440

Publisher: Springer

URL: https://doi.org/10.1007/s00109-012-0976-y

DOI: 10.1007/s00109-012-0976-y

PubMed id: 23183826


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