伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病的发病机制及治疗研究进展

doi:10.16288/j.yczz.23-023

遗传 ›› 2023, Vol. 45 ›› Issue (7): 568-579.doi: 10.16288/j.yczz.23-023

伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病的发病机制及治疗研究进展

张翌(), 吴志英()

浙江大学医学院附属第二医院神经内科，医学遗传科/罕见病诊治中心，杭州 310009

收稿日期:2023-02-01 修回日期:2023-04-27 出版日期:2023-07-20 发布日期:2023-05-09
通讯作者: 吴志英 E-mail:zhangyi_@zju.edu.cn;zhiyingwu@zju.edu.cn
作者简介:张翌，在读博士研究生，专业方向：神经遗传病。E-mail: zhangyi_@zju.edu.cn

Pathogenesis and therapeutic advances of cerebral autosomal- dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Yi Zhang(), Zhi-Ying Wu()

Department of Medical Genetics and Center for Rare Diseases, and Department of Neurology in Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China

Received:2023-02-01 Revised:2023-04-27 Online:2023-07-20 Published:2023-05-09
Contact: Zhi-Ying Wu E-mail:zhangyi_@zju.edu.cn;zhiyingwu@zju.edu.cn

摘要/Abstract

摘要：

伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病(cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy，CADASIL)是成人最常见的遗传性脑小血管病。自CADASIL的致病基因NOTCH3被鉴定以来，大量CADASIL病例被报道，但迄今仍缺乏有效的治疗药物。本文针对CADASIL的疾病模型和致病机制、对症药物治疗及潜在治疗方案研究进展进行综述，以期为后续CADASIL发病机制和治疗研究提供参考。

关键词: 伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病, 发病机制

Abstract:

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease in adults. Many CADASIL cases were reported after NOTCH3 was identified as the causative gene of CADASIL. However, there is still no specific and effective therapies for CADASIL. In this review, we summarize recent research progress on disease models, symptomatic treatments and potential therapies for CADASIL, thereby providing a reference for follow-up CADASIL treatment research.

Key words: CADASIL, pathogenesis

张翌, 吴志英. 伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病的发病机制及治疗研究进展[J]. 遗传, 2023, 45(7): 568-579.

Yi Zhang, Zhi-Ying Wu. Pathogenesis and therapeutic advances of cerebral autosomal- dominant arteriopathy with subcortical infarcts and leukoencephalopathy[J]. Hereditas(Beijing), 2023, 45(7): 568-579.

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参考文献 48

[1]	Rutten JW, Dauwerse HG, Gravesteijn G, van Belzen MJ, van der Grond J, Polke JM, Bernal-Quiros M, Lesnik Oberstein SAJ. Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL. Ann Clin Transl Neurol, 2016, 3(11): 844-853. doi: 10.1002/acn3.2016.3.issue-11
[2]	Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG. Cadasil. Lancet Neurol, 2009, 8(7): 643-653. doi: 10.1016/S1474-4422(09)70127-9 pmid: 19539236
[3]	Chen S, Ni W, Yin XZ, Liu HQ, Lu C, Zheng QJ, Zhao GX, Xu YF, Wu L, Zhang L, Wang N, Li HF, Wu ZY. Clinical features and mutation spectrum in Chinese patients with CADASIL: a multicenter retrospective study. CNS Neurosci Ther, 2017, 23(9): 707-716. doi: 10.1111/cns.12719 pmid: 28710804
[4]	Ni W, Zhang Y, Zhang L, Xie JJ, Li HF, Wu ZY. Genetic spectrum of NOTCH3 and clinical phenotype of CADASIL patients in different populations. CNS Neurosci Ther, 2022, 28(11): 1779-1789. doi: 10.1111/cns.13917 pmid: 35822697
[5]	Tournier-Lasserve E, Joutel A, Melki J, Weissenbach J, Lathrop GM, Chabriat H, Mas JL, Cabanis EA, Baudrimont M, Maciazek J.Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet, 1993, 3(3): 256-259. doi: 10.1038/ng0393-256 pmid: 8485581
[6]	Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cécillion M, Marechal E, Maciazek J, Vayssiere C, Cruaud C, Cabanis EA, Ruchoux MM, Weissenbach J, Bach JF, Bousser MG, Tournier-Lasserve E. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature, 1996, 383(6602): 707-710. doi: 10.1038/383707a0
[7]	Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NST, Abeysinghe S, Krawczak M, Cooper DN. Human gene mutation database (HGMD): 2003 update. Hum Mutat, 2003, 21(6): 577-581.
[8]	Bianchi S, Zicari E, Carluccio A, Di Donato I, Pescini F, Nannucci S, Valenti R, Ragno M, Inzitari D, Pantoni L, Federico A, Dotti MT. CADASIL in central Italy: a retrospective clinical and genetic study in 229 patients. J Neurol, 2015, 262(1): 134-141. doi: 10.1007/s00415-014-7533-2 pmid: 25344745
[9]	Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, Vayssiere C, Cruaud C, Maciazek J, Weissenbach J, Bousser MG, Bach JF, Tournier-Lasserve E. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet, 1997, 350(9090): 1511-1515. doi: 10.1016/S0140-6736(97)08083-5 pmid: 9388399
[10]	Joutel A, Andreux F, Gaulis S, Domenga V, Cecillon M, Battail N, Piga N, Chapon F, Godfrain C, Tournier- Lasserve E. The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. J Clin Invest, 2000, 105(5): 597-605. doi: 10.1172/JCI8047 pmid: 10712431
[11]	Joutel A, Favrole P, Labauge P, Chabriat H, Lescoat C, Andreux F, Domenga V, Cécillon M, Vahedi K, Ducros A, Cave-Riant F, Bousser MG, Tournier-Lasserve E. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet, 2001, 358(9298): 2049-2051. doi: 10.1016/S0140-6736(01)07142-2 pmid: 11755616
[12]	Schweisguth F. Regulation of notch signaling activity. Curr Biol, 2004, 14(3): 129-138. pmid: 14986688
[13]	Monet-Leprêtre M, Haddad I, Baron-Menguy C, Fouillot- Panchal M, Riani M, Domenga-Denier V, Dussaule C, Cognat E, Vinh J, Joutel A. Abnormal recruitment of extracellular matrix proteins by excess Notch3 ECD: a new pathomechanism in CADASIL. Brain, 2013, 136(Pt 6): 1830-1845. doi: 10.1093/brain/awt092 pmid: 23649698
[14]	Schoemaker D, Arboleda-Velasquez JF. Notch3 signaling and aggregation as targets for the treatment of CADASIL and other NOTCH3-associated small-vessel diseases. Am J Pathol, 2021, 191(11): 1856-1870. doi: 10.1016/j.ajpath.2021.03.015 pmid: 33895122
[15]	Cognat E, Baron-Menguy C, Domenga-Denier V, Cleophax S, Fouillade C, Monet-Leprêtre M, Dewerchin M, Joutel A. Archetypal Arg169Cys mutation in NOTCH3 does not drive the pathogenesis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy via a loss-of-function mechanism. Stroke, 2014, 45(3): 842-849. doi: 10.1161/STROKEAHA.113.003339 pmid: 24425116
[16]	Machuca-Parra AI, Bigger-Allen AA, Sanchez AV, Boutabla A, Cardona-Vélez J, Amarnani D, Saint-Geniez M, Siebel CW, Kim LA, D'Amore PA, Arboleda-Velasquez JF. Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL. J Exp Med, 2017, 214(8): 2271-2282. doi: 10.1084/jem.20161715
[17]	Ling C, Liu ZP, Song MS, Zhang WQ, Wang S, Liu XQ, Ma S, Sun SH, Fu LN, Chu Q, Belmonte JCI, Wang ZX, Qu J, Yuan Y, Liu GH. Modeling CADASIL vascular pathologies with patient-derived induced pluripotent stem cells. Protein Cell, 2019, 10(4): 249-271. doi: 10.1007/s13238-019-0608-1 pmid: 30778920
[18]	Dabertrand F, Krøigaard C, Bonev AD, Cognat E, Dalsgaard T, Domenga-Denier V, Hill-Eubanks DC, Brayden JE, Joutel A, Nelson MT. Potassium channelopathy- like defect underlies early-stage cerebrovascular dysfunction in a genetic model of small vessel disease. Proc Natl Acad Sci USA, 2015, 112(7): E796-E805.
[19]	Oka F, Lee JH, Yuzawa I, Li M, von Bornstaedt D, Eikermann-Haerter K, Qin T, Chung DY, Sadeghian H, Seidel JL, Imai T, Vuralli D, Platt RM, Nelson MT, Joutel A, Sakadzic S, Ayata C. CADASIL mutations sensitize the brain to ischemia via spreading depolarizations and abnormal extracellular potassium homeostasis. J Clin Invest, 2022, 132(8): e149759. doi: 10.1172/JCI149759
[20]	Capone C, Dabertrand F, Baron-Menguy C, Chalaris A, Ghezali L, Domenga-Denier V, Schmidt S, Huneau C, Rose-John S, Nelson MT, Joutel A. Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics. Elife, 2016, 5: e17536. doi: 10.7554/eLife.17536
[21]	Yamamoto Y, Kojima K, Taura D, Sone M, Washida K, Egawa N, Kondo T, Minakawa EN, Tsukita K, Enami T, Tomimoto H, Mizuno T, Kalaria RN, Inagaki N, Takahashi R, Harada-Shiba M, Ihara M, Inoue H. Human iPS cell-derived mural cells as an in vitro model of hereditary cerebral small vessel disease. Mol Brain, 2020, 13(1): 38. doi: 10.1186/s13041-020-00573-w pmid: 32188464
[22]	Neves KB, Harvey AP, Moreton F, Montezano AC, Rios FJ, Alves-Lopes R, Nguyen Dinh Cat A, Rocchicciolli P, Delles C, Joutel A, Muir K, Touyz RM. ER stress and Rho kinase activation underlie the vasculopathy of CADASIL. JCI Insight, 2019, 4(23): e131344. doi: 10.1172/jci.insight.131344
[23]	Panahi M, Yousefi Mesri N, Samuelsson EB, Coupland KG, Forsell C, Graff C, Tikka S, Winblad B, Viitanen M, Karlström H, Sundström E, Behbahani H. Differences in proliferation rate between CADASIL and control vascular smooth muscle cells are related to increased TGFbeta expression. J Cell Mol Med, 2018, 22(6): 3016-3024.
[24]	Ghosh M, Balbi M, Hellal F, Dichgans M, Lindauer U, Plesnila N. Pericytes are involved in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Ann Neurol, 2015, 78(6): 887-900. doi: 10.1002/ana.24512 pmid: 26312599
[25]	Dabertrand F, Harraz OF, Koide M, Longden TA, Rosehart AC, Hill-Eubanks DC, Joutel A, Nelson MT.PIP(2) corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.1 activity. Proc Natl Acad Sci USA, 2021, 118(17): e2025998118.
[26]	Hase Y, Chen AQ, Bates LL, Craggs LJL, Yamamoto Y, Gemmell E, Oakley AE, Korolchuk VI, Kalaria RN. Severe white matter astrocytopathy in CADASIL. Brain Pathol, 2018, 28(6): 832-843. doi: 10.1111/bpa.12621
[27]	Kelleher J, Dickinson A, Cain S, Hu YH, Bates N, Harvey A, Ren JZ, Zhang WJ, Moreton FC, Muir KW, Ward C, Touyz RM, Sharma P, Xu QB, Kimber SJ, Wang T. Patient-specific iPSC model of a genetic vascular dementia syndrome reveals failure of mural cells to stabilize capillary structures. Stem Cell Reports, 2019, 13(5): 817-831. doi: S2213-6711(19)30365-0 pmid: 31680059
[28]	Zaucker A, Mercurio S, Sternheim N, Talbot WS, Marlow FL. Notch3 is essential for oligodendrocyte development and vascular integrity in zebrafish. Dis Model Mech, 2013, 6(5): 1246-1259. doi: 10.1242/dmm.012005 pmid: 23720232
[29]	Arboleda-Velasquez JF, Zhou ZP, Shin HK, Louvi A, Kim HH, Savitz SI, Liao JK, Salomone S, Ayata C, Moskowitz MA, Artavanis-Tsakonas S. Linking Notch signaling to ischemic stroke. Proc Natl Acad Sci USA, 2008, 105(12): 4856-4861. doi: 10.1073/pnas.0709867105 pmid: 18347334
[30]	Domenga V, Fardoux P, Lacombe P, Monet M, Maciazek J, Krebs LT, Klonjkowski B, Berrou E, Mericskay M, Li Z, Tournier-Lasserve E, Gridley T, Joutel A. Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev, 2004, 18(22): 2730-2735. doi: 10.1101/gad.308904
[31]	Ruchoux MM, Domenga V, Brulin P, Maciazek J, Limol S, Tournier-Lasserve E, Joutel A. Transgenic mice expressing mutant Notch3 develop vascular alterations characteristic of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Am J Pathol, 2003, 162(1): 329-342. pmid: 12507916
[32]	Monet M, Domenga V, Lemaire B, Souilhol C, Langa F, Babinet C, Gridley T, Tournier-Lasserve E, Cohen- Tannoudji M, Joutel A. The archetypal R90C CADASIL- NOTCH3 mutation retains NOTCH3 function in vivo. Hum Mol Genet, 2007, 16(8): 982-992. doi: 10.1093/hmg/ddm042
[33]	Joutel A, Monet-Leprêtre M, Gosele C, Baron-Menguy C, Hammes A, Schmidt S, Lemaire-Carrette B, Domenga V, Schedl A, Lacombe P, Hubner N. Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease. J Clin Invest, 2010, 120(2): 433-445. doi: 10.1172/JCI39733 pmid: 20071773
[34]	Rutten JW, Klever RR, Hegeman IM, Poole DS, Dauwerse HG, Broos LAM, Breukel C, Aartsma-Rus AM, Verbeek JS, van der Weerd L, van Duinen SG, van den Maagdenberg AMJM, Lesnik Oberstein SAJ. The NOTCH3 score: a pre-clinical CADASIL biomarker in a novel human genomic NOTCH3 transgenic mouse model with early progressive vascular NOTCH3 accumulation. Acta Neuropathol Commun, 2015, 3: 89. doi: 10.1186/s40478-015-0268-1
[35]	Monet-Leprêtre M, Bardot B, Lemaire B, Domenga V, Godin O, Dichgans M, Tournier-Lasserve E, Cohen- Tannoudji M, Chabriat H, Joutel A. Distinct phenotypic and functional features of CADASIL mutations in the Notch3 ligand binding domain. Brain, 2009, 132(Pt 6): 1601-1612. doi: 10.1093/brain/awp049 pmid: 19293235
[36]	Arboleda-Velasquez JF, Manent J, Lee JH, Tikka S, Ospina C, Vanderburg CR, Frosch MP, Rodriguez-Falcon M, Villen J, Gygi S, Lopera F, Kalimo H, Moskowitz MA, Ayata C, Louvi A, Artavanis-Tsakonas S. Hypomorphic Notch3 alleles link Notch signaling to ischemic cerebral small-vessel disease. Proc Natl Acad Sci USA, 2011, 108(21): E128-E135.
[37]	Gu X, Liu XY, Fagan A, Gonzalez-Toledo ME, Zhao LR. Ultrastructural changes in cerebral capillary pericytes in aged Notch3 mutant transgenic mice. Ultrastruct Pathol, 2012, 36(1): 48-55. doi: 10.3109/01913123.2011.620220 pmid: 22292737
[38]	Chinese Society of Neurology, Chinese Stroke Society. Chinese guideline for diagnosis and treatment of cerebral small vessel disease 2020. Chin J Neurol, 2022, 55(8): 807-818.
	中华医学会神经病学分会, 中华医学会神经病学分会脑血管病学组. 中国脑小血管病诊治指南2020. 中华神经科杂志, 2022, 55(8): 807-818.
[39]	Watanabe-Hosomi A, Mizuta I, Koizumi T, Yokota I, Mukai M, Hamano A, Kondo M, Fujii A, Matsui M, Matsuo K, Ito K, Teramukai S, Yamada K, Nakagawa M, Mizuno T. Effect of lomerizine hydrochloride on preventing strokes in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Clin Neuropharmacol, 2020, 43(5): 146-150. doi: 10.1097/WNF.0000000000000402 pmid: 32947425
[40]	Khan MT, Murray A, Smith M. Successful use of intravenous tissue plasminogen activator as treatment for a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: a case report and review of literature. J Stroke Cerebrovasc Dis, 2016, 25(4): e53-e57.
[41]	Dichgans M, Markus HS, Salloway S, Verkkoniemi A, Moline M, Wang Q, Posner H, Chabriat HS. Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL. Lancet Neurol, 2008, 7(4): 310-318. doi: 10.1016/S1474-4422(08)70046-2 pmid: 18296124
[42]	Liu XY, Gonzalez-Toledo ME, Fagan A, Duan WM, Liu YY, Zhang SY, Li B, Piao CS, Nelson L, Zhao LR. Stem cell factor and granulocyte colony-stimulating factor exhibit therapeutic effects in a mouse model of CADASIL. Neurobiol Dis, 2015, 73: 189-203. doi: 10.1016/j.nbd.2014.09.006
[43]	Ping SN, Qiu XC, Kyle M, Hughes K, Longo J, Zhao LR. Stem cell factor and granulocyte colony-stimulating factor promote brain repair and improve cognitive function through VEGF-A in a mouse model of CADASIL. Neurobiol Dis, 2019, 132: 104561. doi: 10.1016/j.nbd.2019.104561
[44]	Ghezali L, Capone C, Baron-Menguy C, Ratelade J, Christensen S, Østergaard Pedersen L, Domenga-Denier V, Pedersen JT, Joutel A. Notch3(ECD) immunotherapy improves cerebrovascular responses in CADASIL mice. Ann Neurol, 2018, 84(2): 246-259. doi: 10.1002/ana.25284 pmid: 30014602
[45]	Oliveira DV, Coupland KG, Shao WC, Jin SB, Del Gaudio F, Wang SL, Fox R, Rutten JW, Sandin J, Zetterberg H, Lundkvist J, Lesnik Oberstein SA, Lendahl U, Karlström H. Active immunotherapy reduces NOTCH3 deposition in brain capillaries in a CADASIL mouse model. EMBO Mol Med, 2022, 15(2): e16556. doi: 10.15252/emmm.202216556
[46]	Rutten JW, Dauwerse HG, Peters DJM, Goldfarb A, Venselaar H, Haffner C, van Ommen GJB, Aartsma-Rus AM, Lesnik Oberstein SAJ. Therapeutic NOTCH3 cysteine correction in CADASIL using exon skipping: in vitro proof of concept. Brain, 2016, 139(Pt 4): 1123-1135. doi: 10.1093/brain/aww011 pmid: 26912635
[47]	Gravesteijn G, Dauwerse JG, Overzier M, Brouwer G, Hegeman I, Mulder AA, Baas F, Kruit MC, Terwindt GM, van Duinen SG, Jost CR, Aartsma-Rus A, Lesnik Oberstein SAJ, Rutten JW. Naturally occurring NOTCH3 exon skipping attenuates NOTCH3 protein aggregation and disease severity in CADASIL patients. Hum Mol Genet, 2020, 29(11): 1853-1863. doi: 10.1093/hmg/ddz285 pmid: 31960911
[48]	Liu Y, Zhou XH, Huang SH, Wang XL. Prime editing: a search and replace tool with versatile base changes. Hereditas(Beijing), 2022, 44(11): 993-1008. doi: 10.16288/j.yczz.22-156 pmid: 36384993
	刘尧, 周先辉, 黄舒泓, 王小龙. 引导编辑:突破碱基编辑类型的新技术. 遗传, 2022, 44(11): 993-1008. doi: 10.16288/j.yczz.22-156 pmid: 36384993

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动物模型	突变基因来源	Notch3胞外结构域沉积、GOM形成	血管平滑肌退化	脑白质病变	NOTCH信号通路异常	参考文献
Notch3st51/Notch3zm斑马鱼	斑马鱼Notch3	-	+	-	+	[28]
NOTCH3KO小鼠	-	-	+	-	-	[29, 30]
TgNotch3R90C小鼠	人NOTCH3	+	+	-	-	[31, 32]
TgNotch3R169C小鼠	大鼠Notch3	+	+	+	-	[33]
TgNotch3R182C小鼠	人NOTCH3	+	-	-	-	[34]
TgNotch3C428S小鼠	人NOTCH3	+	+	-	+	[35]
TgNotch3C455R小鼠	人NOTCH3	+	+	-	+	[36]
TgNotch3R1031C小鼠	人NOTCH3	+	+	-	-	[36]

伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病的发病机制及治疗研究进展

Pathogenesis and therapeutic advances of cerebral autosomal- dominant arteriopathy with subcortical infarcts and leukoencephalopathy

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[2]	王师尧，金巍娜，吴丹. 青少年型神经元蜡样脂褐质沉积病(JNCL)的发病机制[J]. 遗传, 2009, 31(8): 779-784.