气候变化领域集成服务门户(CCPortal): Increased plasmin-mediated proteolysis of L1CAM in a mouse model of idiopathic normal pressure hydrocephalus

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DOI	10.1073/pnas.2010528118
	Increased plasmin-mediated proteolysis of L1CAM in a mouse model of idiopathic normal pressure hydrocephalus
	Yang D.; Yang H.; Luiselli G.; Ogagan C.; Dai H.; Chiu L.; Carroll R.S.; Johnson M.D.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:33
英文摘要	Idiopathic normal pressure hydrocephalus (iNPH) is a common neurological disorder that is characterized by enlarged cerebral ventricles, gait difficulty, incontinence, and dementia. iNPH usually develops after the sixth decade of life in previously asymptomatic individuals. We recently reported that loss-of-function deletions in CWH43 lead to the development of iNPH in a subgroup of patients, but how this occurs is poorly understood. Here, we show that deletions in CWH43 decrease expression of the cell adhesion molecule, L1CAM, in the brains of CWH43 mutant mice and in human HeLa cells harboring a CWH43 deletion. Loss-of-function mutations in L1CAM are a common cause of severe neurodevelopmental defects that include congenital X-linked hydrocephalus. Mechanistically, we find that CWH43 deletion leads to decreased N-glycosylation of L1CAM, decreased association of L1CAM with cell membrane lipid microdomains, increased L1CAM cleavage by plasmin, and increased shedding of cleaved L1CAM in the cerebrospinal fluid. CWH43 deletion also decreased L1CAM nuclear translocation, suggesting decreased L1CAM intracellular signaling. Importantly, the increase in L1CAM cleavage occurred primarily in the ventricular and subventricular zones where brain CWH43 is most highly expressed. Thus, CWH43 deletions may contribute to adult-onset iNPH by selectively downregulating L1CAM in the ventricular and subventricular zone. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	CWH43; Hydrocephalus; L1CAM; Normal pressure hydrocephalus; Plasmin
语种	英语
scopus关键词	cell adhesion molecule; L1CAM protein; unclassified drug; lipid; nerve cell adhesion molecule L1; plasmin; protein binding; RNA; Article; controlled study; CWH43 gene; disease severity; gene; gene deletion; gene expression; gene function; gene loss; glycosylation; HeLa cell line; human; human cell; human tissue; hydrocephalus; intracellular signaling; mental disease; mouse; nonhuman; normotensive hydrocephalus; protein cleavage; protein degradation; protein transport; signal transduction; animal; brain; cerebrospinal fluid pressure; chemistry; down regulation; gene expression regulation; genetics; metabolism; nuclear magnetic resonance imaging; pathology; protein domain; Animals; Brain; Cerebrospinal Fluid Pressure; Down-Regulation; Fibrinolysin; Gene Deletion; Gene Expression Regulation; HeLa Cells; Humans; Hydrocephalus; Lipids; Magnetic Resonance Imaging; Mice; Neural Cell Adhesion Molecule L1; Protein Binding; Protein Domains; RNA
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/251066
作者单位	Department of Neurological Surgery, University of Massachusetts Medical School, University of Massachusetts Memorial Healthcare, Worcester, MA 01655, United States
推荐引用方式 GB/T 7714	Yang D.,Yang H.,Luiselli G.,et al. Increased plasmin-mediated proteolysis of L1CAM in a mouse model of idiopathic normal pressure hydrocephalus[J],2021,118(33).
APA	Yang D..,Yang H..,Luiselli G..,Ogagan C..,Dai H..,...&Johnson M.D..(2021).Increased plasmin-mediated proteolysis of L1CAM in a mouse model of idiopathic normal pressure hydrocephalus.Proceedings of the National Academy of Sciences of the United States of America,118(33).
MLA	Yang D.,et al."Increased plasmin-mediated proteolysis of L1CAM in a mouse model of idiopathic normal pressure hydrocephalus".Proceedings of the National Academy of Sciences of the United States of America 118.33(2021).