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.
Highlights
Parkinson’s disease is the second most common human neurodegenerative disease and is characterised by the preferential loss of dopaminergic neurons in the substantia nigra
Probing of immunoblots with an enhanced green fluorescent protein (EGFP) antibody revealed that they expressed similar levels of exogenous protein and that expression of α-synuclein did not affect expression of the endoplasmic reticulum (ER)–mitochondria tethering proteins vesicle-associated membrane protein-associated protein B (VAPB) and protein tyrosine phosphatase-interacting protein 51 (PTPIP51), of mitofusin-2 which has been proposed as a further ER–mitochondria tether, or of the Sigma-1 receptor which has been linked to ER–mitochondria tethering [5, 19, 29, 86] (Fig. 1a)
Confocal and structured illumination microscopy (SIM) revealed that mitochondria in EGFP-α-synuclein and EGFP-α-synucleinA53T cells had increased circularity (EGFP-α-synucleinA30P displayed a trend for increased circularity) and that mitochondria in wild-type and mutant EGFP-α-synuclein cells had reduced cytosolic distributions (Supplemental Fig. 1b, c)
Summary
Parkinson’s disease is the second most common human neurodegenerative disease and is characterised by the preferential loss of dopaminergic neurons in the substantia nigra. The cell and molecular events that give rise to this neuronal loss are not properly understood but a number of lines of evidence suggest that abnormalities in α-synuclein are central to the disease process. Α-synuclein is the major protein constituent of Lewy bodies and Lewy neurites which are hallmark pathologies of Parkinson’s disease [76, 80]. Overexpression of wild-type and familial mutant α-synuclein can induce aspects of disease in transgenic mice [6, 7, 18]. Despite this evidence, the mechanisms by which altered α-synuclein metabolism might cause disease are not properly understood. Α-synuclein localizes to cytosolic and membrane compartments including synaptic vesicles, mitochondria and the endoplasmic reticulum (ER) (see reviews [32, 33, 91])
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