cddis2016173a.pdf (1.94 MB)
Download file

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

Download (1.94 MB)
journal contribution
posted on 11.07.2016, 14:45 by I. Celardo, A. C. Costa, S. Lehmann, C. Jones, N. Wood, N. E. Mencacci, G. R. Mallucci, S. H. Loh, L. Miguel Martins
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.

History

Citation

Cell Death and Disease, 2016, 7 (6), e2271

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Molecular & Cell Biology

Version

VoR (Version of Record)

Published in

Cell Death and Disease

Publisher

Nature Publishing Group

eissn

2041-4889

Acceptance date

26/05/2016

Copyright date

2016

Available date

11/07/2016

Publisher version

http://www.nature.com/cddis/journal/v7/n6/full/cddis2016173a.html

Language

en

Usage metrics

Categories

Keywords

Licence

Exports