气候变化领域集成服务门户(CCPortal): The Parkinson's disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release

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DOI	10.1073/pnas.2006476118
	The Parkinson's disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release
	Apicco D.J.; Shlevkov E.; Nezich C.L.; Tran D.T.; Guilmette E.; Nicholatos J.W.; Bantle C.M.; Chen Y.; Glajch K.E.; Abraham N.A.; Dang L.T.; Kaynor G.C.; Tsai E.A.; Nguyen K.D.H.; Groot J.; YuTing Liu; Weihofen A.; Hurt J.A.; Runz H.; Hirst W.D.
发表日期	2021
ISSN	00278424
卷号	118 期号:1
英文摘要	Inositol-1,4,5-triphosphate (IP3) kinase B (ITPKB) is a ubiquitously expressed lipid kinase that inactivates IP3, a secondary messenger that stimulates calcium release from the endoplasmic reticulum (ER). Genome-wide association studies have identified common variants in the ITPKB gene locus associated with reduced risk of sporadic Parkinson's disease (PD). Here, we investigate whether ITPKB activity or expression level impacts PD phenotypes in cellular and animal models. In primary neurons, knockdown or pharmacological inhibition of ITPKB increased levels of phosphorylated, insoluble α-synuclein pathology following treatment with α-synuclein preformed fibrils (PFFs). Conversely, ITPKB overexpression reduced PFF-induced α-synuclein aggregation. We also demonstrate that ITPKB inhibition or knockdown increases intracellular calcium levels in neurons, leading to an accumulation of calcium in mitochondria that increases respiration and inhibits the initiation of autophagy, suggesting that ITPKB regulates α-synuclein pathology by inhibiting ER-to-mitochondria calcium transport. Furthermore, the effects of ITPKB on mitochondrial calcium and respiration were prevented by pretreatment with pharmacological inhibitors of the mitochondrial calcium uniporter complex, which was also sufficient to reduce α-synuclein pathology in PFF-treated neurons. Taken together, these results identify ITPKB as a negative regulator of α-synuclein aggregation and highlight modulation of ER-to-mitochondria calcium flux as a therapeutic strategy for the treatment of sporadic PD. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Calcium signaling; Genetics; Mitochondria; Parkinson's disease; α-synuclein
语种	英语
scopus关键词	adeno associated virus vector; adenosine triphosphate; alpha synuclein; calcium; inositol 1,4,5 trisphosphate kinase B; phosphotransferase; unclassified drug; animal cell; animal experiment; animal model; animal tissue; Article; autophagy (cellular); calcium cell level; calcium transport; controlled study; drug effect; embryo; endoplasmic reticulum; enzyme activity; gene knockdown; gene overexpression; human; human cell; human tissue; in vivo study; ITPKB gene; mitochondrial respiration; mouse; nerve cell; nervous system inflammation; neuroprotection; nonhuman; Parkinson disease; priority journal; protein aggregation; protein expression
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/181137
作者单位	Neurodegenerative Diseases Research Unit, Biogen, Cambridge, MA 02142, United States; Biogen Postdoctoral Scientist Program, Biogen, Cambridge, MA 02142, United States; Gene Therapy Accelerator Unit, Biotherapeutics and Medicinal Sciences, Biogen, Cambridge, MA 02142, United States; Multiple Sclerosis and Neurorepair Research Unit, Biogen, Cambridge, MA 02142, United States; Human Genetics, Translational Biology, Biogen, Cambridge, MA 02142, United States; Genome Technologies and Scientific Computing, Translational Biology, Biogen, Cambridge, MA 02142, United States; Biologics Drug Discovery, Biotherapeutics and Medicinal Sciences, Biogen, Cambridge, MA 02142, United States; Human Target Validation Core, Translational Biology, Biogen, Cambridge, MA 02142, United States
推荐引用方式 GB/T 7714	Apicco D.J.,Shlevkov E.,Nezich C.L.,et al. The Parkinson's disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release[J],2021,118(1).
APA	Apicco D.J..,Shlevkov E..,Nezich C.L..,Tran D.T..,Guilmette E..,...&Hirst W.D..(2021).The Parkinson's disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release.Proceedings of the National Academy of Sciences of the United States of America,118(1).
MLA	Apicco D.J.,et al."The Parkinson's disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release".Proceedings of the National Academy of Sciences of the United States of America 118.1(2021).