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Open Access 01-07-2017 | Original Paper

α-Synuclein binds to the ER–mitochondria tethering protein VAPB to disrupt Ca²⁺ homeostasis and mitochondrial ATP production

Authors: Sébastien Paillusson, Patricia Gomez-Suaga, Radu Stoica, Daniel Little, Paul Gissen, Michael J. Devine, Wendy Noble, Diane P. Hanger, Christopher C. J. Miller

Published in: Acta Neuropathologica | Issue 1/2017

Abstract

α-Synuclein is strongly linked to Parkinson’s disease but the molecular targets for its toxicity are not fully clear. However, many neuronal functions damaged in Parkinson’s disease are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling involves close physical associations between the two organelles that are mediated by binding of the integral ER protein vesicle-associated membrane protein-associated protein B (VAPB) to the outer mitochondrial membrane protein, protein tyrosine phosphatase-interacting protein 51 (PTPIP51). VAPB and PTPIP51 thus act as a scaffold to tether the two organelles. Here we show that α-synuclein binds to VAPB and that overexpression of wild-type and familial Parkinson’s disease mutant α-synuclein disrupt the VAPB-PTPIP51 tethers to loosen ER–mitochondria associations. This disruption to the VAPB-PTPIP51 tethers is also seen in neurons derived from induced pluripotent stem cells from familial Parkinson’s disease patients harbouring pathogenic triplication of the α-synuclein gene. We also show that the α-synuclein induced loosening of ER–mitochondria contacts is accompanied by disruption to Ca²⁺ exchange between the two organelles and mitochondrial ATP production. Such disruptions are likely to be particularly damaging to neurons that are heavily dependent on correct Ca²⁺ signaling and ATP.

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Title: α-Synuclein binds to the ER–mitochondria tethering protein VAPB to disrupt Ca2+ homeostasis and mitochondrial ATP production
Authors: Sébastien Paillusson
Patricia Gomez-Suaga
Radu Stoica
Daniel Little
Paul Gissen
Michael J. Devine
Wendy Noble
Diane P. Hanger
Christopher C. J. Miller
Publication date: 01-07-2017
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 1/2017
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-017-1704-z

Keynote webinar | Spotlight on sleep in brain health

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α-Synuclein binds to the ER–mitochondria tethering protein VAPB to disrupt Ca²⁺ homeostasis and mitochondrial ATP production

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

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