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