Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson's disease.
Cell Death Dis
Springer Science and Business Media LLC
MetadataShow full item record
Celardo, I., Costa, A., Lehmann, S., Jones, C., Wood, N., Mencacci, N., Mallucci, G., et al. (2016). Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson's disease.. Cell Death Dis, 7 (6), e2271. https://doi.org/10.1038/cddis.2016.173
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.
Endoplasmic Reticulum, Mitochondria, Animals, Humans, Drosophila melanogaster, Parkinson Disease, Disease Models, Animal, Nerve Degeneration, Ubiquitin-Protein Ligases, Protein-Serine-Threonine Kinases, eIF-2 Kinase, Drosophila Proteins, Membrane Proteins, Signal Transduction, Phosphorylation, Mutation, Unfolded Protein Response, Endoplasmic Reticulum Stress, Neuroprotection
European Research Council (647479)
External DOI: https://doi.org/10.1038/cddis.2016.173
This record's URL: https://www.repository.cam.ac.uk/handle/1810/268490
Attribution 4.0 International, Attribution 4.0 International
Recommended or similar items
The following licence files are associated with this item: