Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia

Literals

• dcterms:publisher
  • Aging Cell
• dcterms:title
  • Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia
• fabio:hasPublicationYear
  • 2022
• dcterms:contributor
  • Gomez-Suaga P. et al.
• bibo:doi
  • 10.1111/acel.13549
• dcterms:creator
  • Gomez-Suaga P.
• ou:bibtex
  • @article{371ed96dae94440d8b393e94991d70c4, title = 'Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia', abstract = 'Hexanucleotide repeat expansions in C9orf72 are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The mechanisms by which the expansions cause disease are not properly understood but a favoured route involves its translation into dipeptide repeat (DPR) polypeptides, some of which are neurotoxic. However, the precise targets for mutant C9orf72 and DPR toxicity are not fully clear, and damage to several neuronal functions has been described. Many of these functions are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. ER-mitochondria signalling requires close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 'tethering' proteins. Here, we show that ER-mitochondria signalling and the VAPB-PTPIP51 tethers are disrupted in neurons derived from induced pluripotent stem (iPS) cells from patients carrying ALS/FTD pathogenic C9orf72 expansions and in affected neurons in mutant C9orf72 transgenic mice. In these mice, disruption of the VAPB-PTPIP51 tethers occurs prior to disease onset suggesting that it contributes to the pathogenic process. We also show that neurotoxic DPRs disrupt the VAPB-PTPIP51 interaction and ER-mitochondria contacts and that this may involve activation of glycogen synthase kinases-3β (GSK3β), a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that these DPRs disrupt delivery of Ca2+ from ER stores to mitochondria, which is a primary function of the VAPB-PTPIP51 tethers. This delivery regulates a number of key neuronal functions that are damaged in ALS/FTD including bioenergetics, autophagy and synaptic function. Our findings reveal a new molecular target for mutant C9orf72-mediated toxicity.', author = '{Gomez Suaga}, Patricia and Gabor Morotz and Andrea Markovinovic and {Martin Guerrero}, Sandra and Elisavet Preza and {Arias Del Castillo}, Natalia and Keith Mayl and Afra Aabdien and Vesela Gesheva and Agnes Nishimura and Ambra Annibali and Younbok Lee and Jackie Mitchell and Selina Wray and Christopher Shaw and Wendy Noble and Christopher Miller', note = 'Funding Information: This work was supported by a Fellowship to PG‐S from the UK Motor Neurone Disease Association (Gomez‐Suaga/Oct17/967/799) and a King's College Patient and Carers Fund award, and by grants from UK Medical Research Council (MR/R022666/1), Alzheimer's Research UK (ARUK‐DC2019‐009, ARUK‐PG2017B‐3), the Alzheimer's Society (AlzSoc‐287) and MNDA (Miller/Oct12/6291) to CCJM. SW and EP are supported by the National Institute for Health Research UCL Hospitals Biomedical Research Centre. The work was also supported by the UK Dementia Research Institute at King's College. We thank George Chennell at the Wohl Cellular Imaging Centre at King{\textquoteright}s College London for help with microscopy and Tilo Kunath (University of Edinburgh) for gift of control iPS cell lines. Funding Information: This work was supported by a Fellowship to PG-S from the UK Motor Neurone Disease Association (Gomez-Suaga/Oct17/967/799) and a King's College Patient and Carers Fund award, and by grants from UK Medical Research Council (MR/R022666/1), Alzheimer's Research UK (ARUK-DC2019-009 -The Dementia Consortium: Alzheimer's Research UK, Abbvie, Astex, Eli Lilly, Eisai, MSD, JPNV and Takeda, ARUK-PG2017B-3), the Alzheimer's Society (AlzSoc-287) and MNDA (Miller/Oct12/6291) to CCJM. SW and EP are supported by the National Institute for Health Research UCL Hospitals Biomedical Research Centre. The work was also supported by the UK Dementia Research Institute at King's College. We thank George Chennell at the Wohl Cellular Imaging Centre at King?s College London for help with microscopy and Tilo Kunath (University of Edinburgh) for gift of control iPS cell lines. [Correction added on 01 February 2022, after first online publication: Acknowledgements section has been modified in this version.] Publisher Copyright: {\textcopyright} 2022 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.', year = '2022', month = feb, doi = '10.1111/acel.13549', language = 'English', volume = '21', journal = 'AGING CELL', issn = '1474-9718', publisher = 'Wiley-Blackwell', number = '2', }
• vivo:identifier
  • 2022-1954
• ou:eid
  • 2-s2.0-85122747982
• bibo:issn
  • 1474-9718
• bibo:eissn
  • 1474-9726
• ou:tipoPublicacion
  • Article
• vcard:url
  • https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85122747982&origin=inward
• ou:urlOrcid
  • https://kclpure.kcl.ac.uk/portal/en/publications/371ed96d-ae94-440d-8b39-3e94991d70c4
• ou:urlScopus
  • https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85122747982&origin=inward
• ou:vecesCitado
  • 31
• bibo:volume
  • 21

Typed Literals

• ou:openaccess
  • True (xsd:boolean)

Relations

• ou:publicadaEnRevista
  • AGING CELL

Inverse Relations

• Has related: ou:tienePublicacion
  • PATRICIA MARÍA GÓMEZ SUAGA