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

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

Research output: Contribution to journalArticlepeer-review

259 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)129–149
Number of pages21
JournalActa Neuropathologica
Volume134
Early online date23 Mar 2017
DOIs
Publication statusPublished - 23 Mar 2017

Keywords

  • Autophagy
  • Axonal transport
  • Calcium signaling
  • Endoplasmic reticulum
  • Mitochondria
  • α-Synuclein

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