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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., Rodolfo, C., Harvey, R. J., & 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
Electronic ISSN 1662-5099
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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