NDLI: Parkinson’s disease-associated mutations in DJ-1 modulate its dimerization in living cells

Content Provider	Springer Nature Link
Author	Repici, Mariaelena Straatman, Kornelis R. Balduccio, Nadia Enguita, Francisco J. Outeiro, Tiago F. Giorgini, Flavia
Copyright Year	2012
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 P158∆ 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.
Starting Page	599
Ending Page	611
Page Count	13
File Format	PDF
ISSN	09462716
Journal	Journal of Molecular Medicine
Volume Number	91
Issue Number	5
e-ISSN	14321440
Language	English
Publisher	Springer-Verlag
Publisher Date	2012-11-27
Publisher Place	Berlin/Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Parkinson’s disease DJ-1 Dimerization Bimolecular fluorescence complementation Molecular Medicine Human Genetics Internal Medicine
Content Type	Text
Resource Type	Article
Subject	Drug Discovery Molecular Medicine Genetics (clinical)

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