eprintid: 1506424 rev_number: 35 eprint_status: archive userid: 608 dir: disk0/01/50/64/24 datestamp: 2016-07-30 22:10:48 lastmod: 2021-09-19 22:53:22 status_changed: 2017-02-24 18:19:42 type: article metadata_visibility: show creators_name: Celardo, I creators_name: Costa, AC creators_name: Lehmann, S creators_name: Jones, C creators_name: Wood, N creators_name: Mencacci, NE creators_name: Mallucci, GR creators_name: Loh, SH creators_name: Martins, LM title: Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson's disease ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F84 note: Copyright © The Author(s) 2016. Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ 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. date: 2016-06 date_type: published official_url: http://doi.org/10.1038/cddis.2016.173 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1139874 doi: 10.1038/cddis.2016.173 pii: cddis2016173 lyricists_name: Mencacci, Niccolo lyricists_name: Wood, Nicholas lyricists_id: NMENC79 lyricists_id: NWWOO43 full_text_status: public publication: Cell Death and Disease volume: 7 article_number: e2271 event_location: England issn: 2041-4889 citation: Celardo, I; Costa, AC; Lehmann, S; Jones, C; Wood, N; Mencacci, NE; Mallucci, GR; ... Martins, LM; + view all <#> Celardo, I; Costa, AC; Lehmann, S; Jones, C; Wood, N; Mencacci, NE; Mallucci, GR; Loh, SH; Martins, LM; - view fewer <#> (2016) Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson's disease. Cell Death and Disease , 7 , Article e2271. 10.1038/cddis.2016.173 <https://doi.org/10.1038/cddis.2016.173>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/1506424/1/Mencacci_cddis2016173a.pdf