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

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1704-z) contains supplementary material, which is available to authorized users.

Mitochondria, OxPhos, and neurodegeneration: cells are not just running out of gas

“…For example, we and others have shown that α-synuclein can translocate to MAM regions (165,166), supporting the reported affinity of α-synuclein for lipid raft-like domains and its previously reported association with mitochondrial membranes. In addition, mutations in α-synuclein alter the activities localized in these domains, such as lipid metabolism (165) and calcium regulation (167).…”

VAP‐SCRN1 interaction regulates dynamic endoplasmic reticulum remodeling and presynaptic function

“…This implies that the cytoplasmicextracellular Ca 2+ concentration gradient is reduced, which could explain the reduction in evoked Ca 2+ response and subsequent decreased SV cycling. Consistently, previous reports in nonneuronal cells showed that VAP-mediated membrane contact sites regulate Ca 2+ homeostasis and that SCRN1 controls Ca 2+ -dependent processes (Way et al, 2002;Lin et al, 2015;Paillusson et al, 2017). It remains poorly understood how prolonged increase in basal Ca 2+ levels leads to reduced SV cycling.…”

Identification of MOSPD2, a novel scaffold for endoplasmic reticulum membrane contact sites

“…VAP proteins build MCSs either by directly interacting with other membrane-anchored proteins such as STARD3 and STARD3NL [10], or by interacting with soluble proteins that can also bind a second organelle, such as STARD11, PTPIP51, OSBP, ORP1L, and ORP3 [11][12][13][14][15][16][17]. MCSs scaffolded by VAPs and their interacting partners are involved in diverse biological functions, such as lipid transport, calcium homeostasis, signaling regulation, autophagy, and endosome dynamics [10][11][12]14,[18][19][20][21][22][23].…”