Format

Send to

Choose Destination
Cell Death Dis. 2016 Jun 23;7(6):e2271. doi: 10.1038/cddis.2016.173.

Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson's disease.

Author information

1
MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
2
Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 3BG, UK.
3
Department of Clinical Neurosciences, University of Cambridge, Clifford Allbutt Building, Cambridge Biomedical Campus, Cambridge CB1 0HN, UK.

Abstract

Mutations in PINK1 and PARKIN cause early-onset Parkinson's disease (PD), thought to be due to mitochondrial toxicity. Here, we show that in Drosophila pink1 and parkin mutants, defective mitochondria also give rise to endoplasmic reticulum (ER) stress signalling, specifically to the activation of the protein kinase R-like endoplasmic reticulum kinase (PERK) branch of the unfolded protein response (UPR). We show that enhanced ER stress signalling in pink1 and parkin mutants is mediated by mitofusin bridges, which occur between defective mitochondria and the ER. Reducing mitofusin contacts with the ER is neuroprotective, through suppression of PERK signalling, while mitochondrial dysfunction remains unchanged. Further, both genetic inhibition of dPerk-dependent ER stress signalling and pharmacological inhibition using the PERK inhibitor GSK2606414 were neuroprotective in both pink1 and parkin mutants. We conclude that activation of ER stress by defective mitochondria is neurotoxic in pink1 and parkin flies and that the reduction of this signalling is neuroprotective, independently of defective mitochondria. A video abstract for this article is available online in the supplementary information.

PMID:
27336715
PMCID:
PMC5143399
DOI:
10.1038/cddis.2016.173
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center