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Distinct Mechanisms of Pathogenic DJ-1 Mutations in Mitochondrial Quality Control

Strobbe, D; Robinson, A A; Harvey, K; Rossi, L; Ferraina, C; De Biase, V; Rodolfo, C; Harvey, R J; Campanella, M

Authors

D Strobbe

A A Robinson

K Harvey

L Rossi

C Ferraina

V De Biase

C Rodolfo

R J Harvey

M Campanella



Abstract

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-1M26I 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-1D149A 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.

Citation

Strobbe, D., Robinson, A. A., Harvey, K., Rossi, L., Ferraina, C., De Biase, V., …Campanella, M. (in press). Distinct Mechanisms of Pathogenic DJ-1 Mutations in Mitochondrial Quality Control. Frontiers in Molecular Neuroscience, 11, 68. https://doi.org/10.3389/fnmol.2018.00068

Journal Article Type Article
Acceptance Date Feb 19, 2018
Deposit Date Apr 6, 2018
Publicly Available Date Apr 6, 2018
Journal Frontiers in Molecular Neuroscience
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 11
Pages 68
DOI https://doi.org/10.3389/fnmol.2018.00068
Public URL https://rvc-repository.worktribe.com/output/1388547

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