Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca2+ and synaptic defects
dc.contributor.author | Markovinovic, A | |
dc.contributor.author | Martín-Guerrero, SM | |
dc.contributor.author | Mórotz, GM | |
dc.contributor.author | Salam, S | |
dc.contributor.author | Gomez-Suaga, P | |
dc.contributor.author | Paillusson, S | |
dc.contributor.author | Greig, J | |
dc.contributor.author | Lee, Y | |
dc.contributor.author | Mitchell, JC | |
dc.contributor.author | Noble, W | |
dc.contributor.author | Miller, CCJ | |
dc.date.accessioned | 2024-02-26T10:54:15Z | |
dc.date.issued | 2024-02-23 | |
dc.date.updated | 2024-02-26T08:02:15Z | |
dc.description.abstract | Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are clinically linked major neurodegenerative diseases. Notably, TAR DNA-binding protein-43 (TDP43) accumulations are hallmark pathologies of FTD/ALS and mutations in the gene encoding TDP43 cause familial FTD/ALS. There are no cures for FTD/ALS. FTD/ALS display damage to a broad range of physiological functions, many of which are regulated by signaling between the endoplasmic reticulum (ER) and mitochondria. This signaling is mediated by the VAPB-PTPIP51 tethering proteins that serve to recruit regions of ER to the mitochondrial surface so as to facilitate inter-organelle communications. Several studies have now shown that disrupted ER-mitochondria signaling including breaking of the VAPB-PTPIP51 tethers are features of FTD/ALS and that for TDP43 and other familial genetic FTD/ALS insults, this involves activation of glycogen kinase-3β (GSK3β). Such findings have prompted suggestions that correcting damage to ER-mitochondria signaling and the VAPB-PTPIP51 interaction may be broadly therapeutic. Here we provide evidence to support this notion. We show that overexpression of VAPB or PTPIP51 to enhance ER-mitochondria signaling corrects mutant TDP43 induced damage to inositol 1,4,5-trisphosphate (IP3) receptor delivery of Ca2+ to mitochondria which is a primary function of the VAPB-PTPIP51 tethers, and to synaptic function. Moreover, we show that ursodeoxycholic acid (UDCA), an FDA approved drug linked to FTD/ALS and other neurodegenerative diseases therapy and whose precise therapeutic target is unclear, corrects TDP43 linked damage to the VAPB-PTPIP51 interaction. We also show that this effect involves inhibition of TDP43 mediated activation of GSK3β. Thus, correcting damage to the VAPB-PTPIP51 tethers may have therapeutic value for FTD/ALS and other age-related neurodegenerative diseases. | en_GB |
dc.description.sponsorship | Medical Research Council (MRC) | en_GB |
dc.description.sponsorship | Alzheimer’s Disease Society | en_GB |
dc.description.sponsorship | Alzheimer’s Research UK | en_GB |
dc.identifier.citation | Vol. 12(1), article 32 | en_GB |
dc.identifier.doi | https://doi.org/10.1186/s40478-024-01742-x | |
dc.identifier.grantnumber | MR/R022666/1 | en_GB |
dc.identifier.grantnumber | AlzSoc-287 | en_GB |
dc.identifier.grantnumber | ARUK-PG2017B-3 | en_GB |
dc.identifier.grantnumber | ARUK-DC2019-009 | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/135398 | |
dc.identifier | ORCID: 0000-0002-7898-4295 (Noble, Wendy) | |
dc.language.iso | en | en_GB |
dc.publisher | BMC | en_GB |
dc.rights | © The Author(s) 2024. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. | en_GB |
dc.subject | Neurodegenerative diseases | en_GB |
dc.subject | Frontotemporal dementia | en_GB |
dc.subject | Amyotrophic lateral sclerosis | en_GB |
dc.subject | TDP43 | en_GB |
dc.subject | Alzheimer’s disease | en_GB |
dc.subject | Parkinson’s disease | en_GB |
dc.title | Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca2+ and synaptic defects | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2024-02-26T10:54:15Z | |
dc.identifier.issn | 2051-5960 | |
exeter.article-number | 32 | |
dc.description | This is the final version. Available on open access from BMC via the DOI in this record | en_GB |
dc.description | Data availability: The datasets used and/or analysed during the current study are available from the corresponding authors on reasonable request. | en_GB |
dc.identifier.journal | Acta Neuropathologica Communications | en_GB |
dc.relation.ispartof | Acta Neuropathologica Communications, 12(1) | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2024-02-05 | |
dcterms.dateSubmitted | 2023-09-20 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2024-02-05 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2024-02-26T10:51:38Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2024-02-26T10:54:19Z | |
refterms.panel | A | en_GB |
refterms.dateFirstOnline | 2024-02-23 |
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in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The
Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available
in this article, unless otherwise stated in a credit line to the data.