title: Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson's disease.
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.
authors.affiliation: MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: I
authors.initials: I
authors.lastname: Celardo
authors.affiliation: MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: A C
authors.initials: AC
authors.lastname: Costa
authors.affiliation: MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: S
authors.initials: S
authors.lastname: Lehmann
authors.affiliation: MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: C
authors.initials: C
authors.lastname: Jones
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: N
authors.initials: N
authors.lastname: Wood
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: N E
authors.initials: NE
authors.lastname: Mencacci
authors.affiliation: MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.|Department of Clinical Neurosciences, University of Cambridge, Clifford Allbutt Building, Cambridge Biomedical Campus, Cambridge CB1 0HN, UK.
authors.forename: G R
authors.initials: GR
authors.lastname: Mallucci
authors.affiliation: MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: S H Y
authors.initials: SH
authors.lastname: Loh
authors.affiliation: MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: L M
authors.initials: LM
authors.lastname: Martins
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism* / Q000648:ultrastructure; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D000066829:Neuroprotection; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D019892:eIF-2 Kinase; C527117:Marf protein, Drosophila; C111567:parkin protein; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase