α-Synuclein binds to the ER-mitochondria tethering protein VAPB to disrupt Ca2+homeostasis and mitochondrial ATP production.
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.
Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 5 Cutcombe road, London, SE5 9RX, UK.
Sébastien
S
Paillusson
Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 5 Cutcombe road, London, SE5 9RX, UK.
Patricia
P
Gomez-Suaga
Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 5 Cutcombe road, London, SE5 9RX, UK.
Radu
R
Stoica
MRC Laboratory of Molecular Cell Biology, University College London, London, UK.
Daniel
D
Little
MRC Laboratory of Molecular Cell Biology, University College London, London, UK.
Paul
P
Gissen
Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.
Michael J
MJ
Devine
Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 5 Cutcombe road, London, SE5 9RX, UK.
Wendy
W
Noble
Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 5 Cutcombe road, London, SE5 9RX, UK.
Diane P
DP
Hanger
Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 5 Cutcombe road, London, SE5 9RX, UK. chris.miller@kcl.ac.uk.
Christopher C J
CCJ
Miller
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002413:Cations, Divalent / Q000378:metabolism; D045744:Cell Line, Tumor; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D057809:HEK293 Cells; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D033921:Vesicular Transport Proteins / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D002413:Cations, Divalent; D024101:Mitochondrial Proteins; C497604:SNCA protein, human; C496748:VAPB protein, human; D033921:Vesicular Transport Proteins; D051844:alpha-Synuclein; D000255:Adenosine Triphosphate; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D017027:Protein Tyrosine Phosphatases; C515449:RMDN3 protein, human; D002118:Calcium
Autophagy; Axonal transport; Calcium signaling; Endoplasmic reticulum; Mitochondria; α-Synuclein