Authors
Kerry Blair, Philippe Gosset, Raquel Martinez-Serra, Gábor M Mórotz, Sandra M Martín-Guerrero, Patricia Gomez-Suaga, Joseph Atherton, Jacqueline C Mitchell, Wendy Noble, Christopher C J Miller, Andrea Markovinovic
Published in
Cells. Volume 15. Issue 17. Aug 26, 2026. Epub Aug 26, 2026.
Abstract
Signalling between the ER and mitochondria regulates a number of key cellular functions that are damaged in frontotemporal dementia and related amyotrophic lateral sclerosis (FTD/ALS). This signalling involves close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 ER-mitochondria "tethering" proteins. A number of studies have shown that mutant genes which cause familial FTD/ALS disrupt the VAPB-PTPIP51 tethers and that this involves activation of GSK3β. TDP43 is one such mutant and altered TDP43 metabolism is central to FTD/ALS pathogenesis. Loss of Sigma-1 receptor function is also seen in FTD/ALS and there is evidence that Sigma-1 receptor agonists can repair damaged ER-mitochondria signalling. However, the underlying mechanisms are not properly understood. In this study, we show that the reference Sigma-1 receptor agonist PRE-084 stimulates VAPB-PTPIP51 binding and rescues FTD/ALS mutant TDP43-induced disruption to the VAPB-PTPIP51 interaction and linked ER-mitochondria Ca2+ delivery. We also show that these effects involve inhibition of the kinase GSK3β, a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that ANAVEX2-73, a further Sigma-1 receptor agonist which is in clinical trials for Alzheimer's disease, also stimulates VAPB-PTPIP51 binding via GSK3β inhibition. Our findings provide novel insights into the mechanisms by which Sigma-1 receptor agonists influence defective ER-mitochondria signalling in FTD/ALS.
PMID:
42738830
Bibliographic data and abstract were imported from PubMed on 18 Oct 2026.
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