期刊
ACTA NEUROPATHOLOGICA
卷 134, 期 1, 页码 129-149出版社
SPRINGER
DOI: 10.1007/s00401-017-1704-z
关键词
alpha-Synuclein; Endoplasmic reticulum; Mitochondria; Axonal transport; Calcium signaling; Autophagy
资金
- Parkinson's UK
- Alzheimer's Research UK
- UK Medical Research Council
- Wellcome Trust
- Innovative Medicines Initiative Joint Undertaking under European Union [115439]
- EFPIA
- Wellcome Trust [106713/Z/14/Z] Funding Source: Wellcome Trust
- MRC [G0501573] Funding Source: UKRI
- Alzheimers Research UK [ARUK-PG2017B-3, ART-PPG2011A-14, ARUK-EG2013B-1, ARUK-PG2014-5] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V0217] Funding Source: researchfish
- Medical Research Council [G0501573] Funding Source: researchfish
- National Institute for Health Research [CL-2012-21-005] Funding Source: researchfish
- Parkinson's UK [G-1308] Funding Source: researchfish
- Wellcome Trust [106713/Z/14/Z] Funding Source: researchfish
alpha-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 alpha-synuclein binds to VAPB and that overexpression of wild-type and familial Parkinson's disease mutant alpha-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 alpha-synuclein gene. We also show that the alpha-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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