Journal
FRONTIERS IN MOLECULAR NEUROSCIENCE
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fnmol.2018.00068
Keywords
mitochondria; mitophagy; DJ-1; DJBP/EFCAB6; PARK7; SUMO-1
Categories
Funding
- Biotechnology and Biological Sciences Research Council [BB/M010384/1]
- Medical Research Council [G1100809/2]
- Bloomsbury Colleges Consortium Ph.D. Studentship Scheme
- Petplan Charitable Trust
- Umberto Veronesi Foundation
- Marie Curie Actions and LAM-Bighi Grant Initiative
- FIRB-Research Grant Consolidator Grant 2 [RBFR13P392]
- Italian Ministry of Health [IFO14/01/R/52]
- Austrian Science Fund (FWF) [V216-B13]
- MRC Ph.D. Studentship
- MRC [MR/M00676X/1] Funding Source: UKRI
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The deglycase and chaperone protein DJ-1 is pivotal for cellular oxidative stress responses and mitochondrial quality control. Mutations in PARK7, encoding DJ-1, are associated with early-onset familial Parkinson's disease and lead to pathological oxidative stress and/or disrupted protein degradation by the proteasome. The aim of this study was to gain insights into the pathogenic mechanisms of selected DJ-1 missense mutations, by characterizing protein-protein interactions, core parameters of mitochondrial function, quality control regulation via autophagy, and cellular death following dopamine accumulation. We report that the DJ-1(M26I) mutant influences DJ-1 interactions with SUMO-1, in turn enhancing removal of mitochondria and conferring increased cellular susceptibility to dopamine toxicity. By contrast, the DJ-1(D149A) mutant does not influence mitophagy, but instead impairs Ca2+ dynamics and free radical homeostasis by disrupting DJ-1 interactions with a mitochondrial accessory protein known as DJ-1-binding protein (DJBP/EFCAB6). Thus, individual DJ-1 mutations have different effects on mitochondrial function and quality control, implying mutation-specific pathomechanisms converging on impaired mitochondrial homeostasis.
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