Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca2+ and synaptic defects

Literals

• vcard:url
  • https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85185963881&origin=inward
• bibo:eissn
  • 2051-5960
• bibo:doi
  • 10.1186/s40478-024-01742-x
• ou:eid
  • 2-s2.0-85185963881
• dcterms:creator
  • Markovinovic A.
• dcterms:contributor
  • Markovinovic A. et al.
• ou:bibtex
  • @article{f26a07a645114578a6be1e6066db7c75, title = 'Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca2+ and synaptic defects', 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-3 (GSK3). 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 GSK3. Thus, correcting damage to the VAPB-PTPIP51 tethers may have therapeutic value for FTD/ALS and other age-related neurodegenerative diseases.', author = 'Andrea Markovinovic and {Martin Guerrero}, Sandra and Gabor Morotz and Shaakir Salam and {Gomez Suaga}, Patricia and Sebastien Paillusson and Jenny Greig and Younbok Lee and Jackie Mitchell and Wendy Noble and Christopher Miller', year = '2024', month = feb, day = '23', language = 'English', journal = 'Acta Neuropathologica Communications', issn = '2051-5960', publisher = 'BioMed Central', }
• fabio:hasPublicationYear
  • 2024
• vivo:identifier
  • 2024-1010
• dcterms:publisher
  • Acta Neuropathologica Communications
• ou:tipoPublicacion
  • Article
• dcterms:title
  • Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca2+ and synaptic defects
• ou:urlOrcid
  • https://kclpure.kcl.ac.uk/portal/en/publications/f26a07a6-4511-4578-a6be-1e6066db7c75
• ou:urlScopus
  • https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85185963881&origin=inward
• bibo:volume
  • 12

Typed Literals

• ou:openaccess
  • True (xsd:boolean)
• ou:vecesCitado
  • 14 (xsd:integer)

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• ou:publicadaEnRevista
  • Acta Neuropathologica Communications

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  • PATRICIA MARÍA GÓMEZ SUAGA