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Pathology involves degeneration of vascular smooth muscle cells, yet the mechanisms remain unclear. Using CADASIL transgenic and mutant cell models, the study shows that reduced NOTCH3 SUMOylation impairs NOTCH3 signaling, compromising cell survival and proliferation, and that SUMO1 overexpression rescues cleavage, transcriptional activity, and viability.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/reduced-sumoylation-impairs-notch3-signaling-and-cell-survival-in-the-pathogenesis-of-cadasil/442244/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/reduced-sumoylation-impairs-notch3-signaling-and-cell-survival-in-the-pathogenesis-of-cadasil/442244.png","ImageObject",300,407,{"name":92,"@type":93},"Aran","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-30","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":8},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What causes CADASIL and what major clinical outcomes does it lead to?","Question",{"text":112,"@type":113},"CADASIL is caused by NOTCH3 mutations and results in recurrent ischemic strokes and progressive cognitive impairment, often with early disability. 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Cell Communication and Signaling (2026) 24:3  \n[https://doi.org/10.1186/s12964-025-02556-7](https://doi.org/10.1186/s12964-025-02556-7)  \nCell Communication and Signaling  \nRESEARCH Open Access  \nReduced SUMOylation impairs NOTCH3 signaling and cell survival in the pathogenesisofCADASIL  \nLijun Long 1†, Danni Wu 1†, Xiaoyan Xiong 1, Huihui Xiong2, Xuecheng Qiu3,4,5*† and Suning Ping 1,2*†  \nAbstract  \nCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease caused by NOTCH3 mutation. The condition leads to recurrent ischemic strokes, vascular dementia, early-onset and high disability, and its prevalence has long been underestimated. Pathologically, CADASIL involves the degeneration and loss of brain vascular smooth muscle cells (VSMCs), but the mechanisms remain unclear. Using a transgenic mouse model of CADASIL (NOTCH3-R545C) and NOTCH3 mutant (R90C and R544C) cell models, the study identifies impaired NOTCH3 signaling, resulting from reduced SUMOylation, as a pivotal pathogenic mechanism that compromises cell survival and proliferation. We found that the NOTCH3-R545C mice exhibited anxiety-like behaviors, spatial working memory deficits, and reduced mural cell coverage. In primary VSMCs and HEK293 cells, the NOTCH3 mutation diminished cell viability, proliferation and NOTCH3 cleavage. Mechanistically, NOTCH3 mutations reduced NOTCH3 SUMOylation. This reduction diminished the interaction between the NOTCH3 intracellular domain (NOTCH3ICD) and the transcription factor RBPjκ, thereby impairing downstream NOTCH3 signaling. Overexpression of the SUMOylation molecule SUMO1 restored NOTCH3 cleavage, stability, transcriptional activity, target gene expression, and cell survival/proliferation. In contrast, the deSUMOylation enzyme SENP1 and SUMOylation-deficient NOTCH3 mutants exacerbated these impairments.  \nThese findings demonstrate that reversible SUMOylation of NOTCH3 serves as a critical regulator of VSMC homeostasis, with SUMO1 and SENP1 functioning as key mediators. This study provides novel insights into CADASIL pathogenesis by linking NOTCH3 SUMOylation to vascular dysfunction and further highlights SUMOylation as a potential target for the therapeutic development of CADASIL.  \nKeywords CADASIL, SUMOylation, Vascular smooth muscle cell, NOTCH3 cleavage  \n\n| †Lijun Long and Danni Wu contributed equally to this work. |\n| --- |\n| †Xuecheng Qiu and Suning Ping jointly supervised this work. |\n\n*Correspondence:  \nXuecheng Qiu [qiuxuecheng1990@163.com](qiuxuecheng1990@163.com)[ ](qiuxuecheng1990@163.com)Suning Ping [pingsn3@mail.sysu.edu.cn](pingsn3@mail.sysu.edu.cn)  \n1Neurobiology Research Center, School of Medicine, Shenzhen Campus of SunYat-Sen University, No. 66, Gongchang Road, Guangming District, Shenzhen, Guangdong 518107, China  \n2Department of Histology and Embryology, School of Medicine, Shenzhen Campus of SunYat-Sen University, No. 66, Gongchang Road, Guangming District, Shenzhen, Guangdong 518107, China  \n3Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou, Jiangsu, China  \n4Department of Biochemistry, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, Jiangsu, China  \n5National Demonstration Center for Experimental Basic Medical Science Education, Xuzhou Medical University, Xuzhou, Jiangsu, China  \n© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third ","cbCailtE9DDAi0dG","https://ap.wps.com/l/cbCailtE9DDAi0dG","pdf",9444474,"English","# Abstract\n# Introduction\n## Clinical features and unmet need\n## NOTCH3 mutations and CADASIL pathology\n## Study rationale","[{\"question\":\"What causes CADASIL and what major clinical outcomes does it lead to?\",\"answer\":\"CADASIL is caused by NOTCH3 mutations and results in recurrent ischemic strokes and progressive cognitive impairment, often with early disability. The condition is frequently misdiagnosed and its prevalence is underestimated.\"},{\"question\":\"How does this study connect SUMOylation to NOTCH3 signaling in CADASIL?\",\"answer\":\"The study identifies impaired NOTCH3 signaling as a consequence of reduced NOTCH3 SUMOylation. This reduction weakens the interaction between the NOTCH3 intracellular domain and RBPjκ, thereby suppressing downstream signaling.\"},{\"question\":\"What experimental evidence supports that SUMO1 can rescue CADASIL-relevant cellular defects?\",\"answer\":\"Overexpressing SUMO1 restores NOTCH3 cleavage, stability, transcriptional activity, target gene expression, and cell survival/proliferation. In contrast, SENP1 or SUMOylation-deficient NOTCH3 mutants worsen these impairments.\"}]","Reduced SUMOylation impairs NOTCH3 signaling and cell survival in the pathogenesis of CADASIL | PDF",1790699556,48]