1. Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca 2+ and synaptic defects.
- Author
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Markovinovic A, Martín-Guerrero SM, Mórotz GM, Salam S, Gomez-Suaga P, Paillusson S, Greig J, Lee Y, Mitchell JC, Noble W, and Miller CCJ
- Subjects
- Humans, Calcium metabolism, Endoplasmic Reticulum metabolism, Glycogen Synthase Kinase 3 beta metabolism, Mitochondria metabolism, Protein Tyrosine Phosphatases metabolism, Synapses pathology, TDP-43 Proteinopathies metabolism, Amyotrophic Lateral Sclerosis pathology, Frontotemporal Dementia genetics, Frontotemporal Dementia metabolism, Neurodegenerative Diseases metabolism, Vesicular Transport Proteins genetics
- 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 Ca
2+ 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., (© 2024. The Author(s).)- Published
- 2024
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