气候变化领域集成服务门户(CCPortal): S-nitrosylated TDP-43 triggers aggregation, cell-to-cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD

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DOI	10.1073/pnas.2021368118
	S-nitrosylated TDP-43 triggers aggregation, cell-to-cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD
	Pirie E.; Oh C.-K.; Zhang X.; Han X.; Cieplak P.; Scott H.R.; Deal A.K.; Ghatak S.; Martinez F.J.; Yeo G.W.; Yates J.R.; III; Nakamura T.; Lipton S.A.
发表日期	2021
ISSN	00278424
卷号	118 期号:11
英文摘要	Rare genetic mutations result in aggregation and spreading of cognate proteins in neurodegenerative disorders; however, in the absence of mutation (i.e., in the vast majority of "sporadic" cases), mechanisms for protein misfolding/aggregation remain largely unknown. Here, we show environmentally induced nitrosative stress triggers protein aggregation and cell-to-cell spread. In patient brains with amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), aggregation of the RNA-binding protein TDP- 43 constitutes a major component of aberrant cytoplasmic inclusions. We identify a pathological signaling cascade whereby reactive nitrogen species cause S-nitrosylation of TDP-43 (forming SNO-TDP-43) to facilitate disulfide linkage and consequent TDP- 43 aggregation. Similar pathological SNO-TDP-43 levels occur in postmortem human FTD/ALS brains and in cell-based models, including human-induced pluripotent stem cell (hiPSC)-derived neurons. Aggregated TDP-43 triggers additional nitrosative stress, representing positive feed forward leading to further SNO-TDP-43 formation and disulfide-linked oligomerization/aggregation. Critically, we show that these redox reactions facilitate cell spreading in vivo and interfere with the TDP-43 RNA-binding activity, affecting SNMT1 and phospho-(p)CREB levels, thus contributing to neuronal damage in ALS/FTD disorders. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Aggregation; S-nitrosylation; Spread; TDP-43 proteinopathy
语种	英语
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/180217
作者单位	Department of Cellular and Molecular Medicine, Biomedical Sciences Graduate Program, University of California San Diego, San Diego, CA 92093, United States; Department of Molecular Medicine, The Scripps Research Institute, San Diego, CA 92037, United States; Department of Neuroscience, The Scripps Research Institute, San Diego, CA 92037, United States; Neuroscience Translational Center, The Scripps Research Institute, San Diego, CA 92037, United States; Bioinformatics and Structural Biology Program, Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA 92037, United States; Department of Neurosciences, University of California San Diego School of Medicine, San Diego, CA 92093, United States
推荐引用方式 GB/T 7714	Pirie E.,Oh C.-K.,Zhang X.,et al. S-nitrosylated TDP-43 triggers aggregation, cell-to-cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD[J],2021,118(11).
APA	Pirie E..,Oh C.-K..,Zhang X..,Han X..,Cieplak P..,...&Lipton S.A..(2021).S-nitrosylated TDP-43 triggers aggregation, cell-to-cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD.Proceedings of the National Academy of Sciences of the United States of America,118(11).
MLA	Pirie E.,et al."S-nitrosylated TDP-43 triggers aggregation, cell-to-cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD".Proceedings of the National Academy of Sciences of the United States of America 118.11(2021).