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CADASIL: Molecular Mechanisms and Animal Models

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Animal Models of Dementia

Part of the book series: Neuromethods ((NM,volume 48))

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Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a human genetic syndrome that causes multiple small strokes, due to a single-gene, autosomal dominant mutation with 100% penetrance. CADASIL mutations encode amino acid substitutions that increase or decrease the number of cysteines within the extracellular epidermal growth factor (EGF) repeat domain of the NOTCH3 receptor protein. Histological studies of CADASIL patients have shown a characteristic accumulation of granular osmiophilic material surrounding the arterial smooth muscle cells, and the degeneration and death of some of these smooth muscle cells. The adjacent endothelial cells appear normal. The result is occasional occlusion of small arteries, producing small infarcts throughout the body, particularly in subcortical white matter in the brain in persons over 50 years of age. Several experimental models related to CADASIL have been investigated, including transgenic mice, knockout mice, cell line expression systems, and Drosophila mutants. None of these models reproduce all the characteristics of human CADASIL, but taken together they have provided an increasingly detailed picture. It is clear that continuing NOTCH3 signaling is required in adult mammalian arterial smooth muscle cells to maintain their survival, differentiation, and normal responses to injury and mechanical stress, particularly in the smaller arteries. In these respects, the characteristics of CADASIL are consistent with a partial loss of NOTCH3 signaling. However, attempts to confirm a loss of NOTCH3 signaling by CADASIL alleles in cell culture have led to mixed results. CADASIL patients do consistently exhibit extracellular accumulation of granular osmiophilic material that contains the extracellular (but not the intracellular) domain of the NOTCH3 receptor. Moreover, the accumulation of the extracellular domain of NOTCH3 has been reproduced in some transgenic mice, as well as in a cell culture model. This gradual accumulation of extracellular aggregates of the NOTCH3 extracellular domain may interfere with NOTCH signaling and may help to explain the characteristically late onset of symptoms of CADASIL. In any case, the well-defined cellular and molecular defects in CADASIL provide a promising area for further research, and the location of the affected cell type could facilitate future drug treatments for this disease.

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References

  1. Razvi SS, Bone I (2006) Single gene disorders causing ischaemic stroke. J Neurol 253:685–700

    PubMed  Google Scholar 

  2. Wang QK (2005) Update on the molecular genetics of vascular anomalies. Lymphat Res Biol 3:226–233

    PubMed  CAS  Google Scholar 

  3. Kalaria RN, Viitanen M, Kalimo H, Dichgans M, Tabira T (2004) The pathogenesis of CADASIL: an update. J Neurol Sci 226:35–39

    PubMed  CAS  Google Scholar 

  4. Joutel A, Corpechot C, Ducros A, et al (1996) Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383:707–710

    PubMed  CAS  Google Scholar 

  5. Joutel A, Vahedi K, Corpechot C, et al (1997) Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 350:1511–1515

    PubMed  CAS  Google Scholar 

  6. Fryxell KJ, Soderlund M, Jordan TV (2001) An animal model for the molecular genetics of CADASIL. (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Stroke 32:6–11

    PubMed  CAS  Google Scholar 

  7. Ruchoux MM, Brulin P, Leteurtre E, Maurage CA (2000) Skin biopsy value and leukoaraiosis. Ann NY Acad Sci 903:285–292

    PubMed  CAS  Google Scholar 

  8. Peters N, Opherk C, Bergmann T, Castro M, Herzog J, Dichgans M (2005) Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol 62:1091–1094

    PubMed  Google Scholar 

  9. Choi EJ, Choi CG, Kim JS (2005) Large cerebral artery involvement in CADASIL. Neurology 65:1322–1324

    PubMed  Google Scholar 

  10. Dichgans M (2007) Genetics of ischaemic stroke. Lancet Neurol 6:149–161

    PubMed  CAS  Google Scholar 

  11. Razvi SS, Davidson R, Bone I, Muir KW (2005) The prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the west of Scotland. J Neurol Neurosurg Psychiatry 76:739–741

    PubMed  CAS  Google Scholar 

  12. Razvi SS, Davidson R, Bone I, Muir KW (2005) Is inadequate family history a barrier to diagnosis in CADASIL? Acta Neurol Scand 112:323–326

    PubMed  CAS  Google Scholar 

  13. Pandey T, Abubacker S (2006) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: an imaging mimic of multiple sclerosis. A report of two cases. Med Princ Pract 15:391–395

    PubMed  Google Scholar 

  14. O’Riordan S, Nor AM, Hutchinson M (2002) CADASIL imitating multiple sclerosis: the importance of MRI markers. Mult Scler 8:430–432

    PubMed  Google Scholar 

  15. Oberstein SA, Ferrari MD, Bakker E, et al (1999) Diagnostic Notch3 sequence analysis in CADASIL: three new mutations in Dutch patients. Dutch CADASIL Research Group. Neurology 52:1913–1915

    PubMed  CAS  Google Scholar 

  16. Dotti MT, Federico A, Mazzei R, et al (2005) The spectrum of Notch3 mutations in 28 Italian CADASIL families. J Neurol Neurosurg Psychiatry 76:736–738

    PubMed  CAS  Google Scholar 

  17. Markus HS, Martin RJ, Simpson MA, et al (2002) Diagnostic strategies in CADASIL. Neurology 59:1134–1138

    PubMed  CAS  Google Scholar 

  18. Lee YC, Yang AH, Liu HC, et al (2006) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: two novel mutations in the NOTCH3 gene in Chinese. J Neurol Sci 246:111–115

    PubMed  CAS  Google Scholar 

  19. Pescini F, Bianchi S, Salvadori E, et al (2008) A pathogenic mutation on exon 21 of the NOTCH3 gene causing CADASIL in an octogenarian paucisymptomatic patient. J Neurol Sci 267:170–173

    PubMed  CAS  Google Scholar 

  20. Vikelis M, Papatriantafyllou J, Karageorgiou CE (2007) A novel CADASIL-causing mutation in a stroke patient. Swiss Med Wkly 137:323–325

    PubMed  Google Scholar 

  21. Ragno M, Cacchio G, Fabrizi GM, et al (2007) Clinical presentation of CADASIL in an Italian patient with a rare Gly528Cys exon 10 NOTCH3 gene mutation. Neurol Sci 28:181–184

    PubMed  CAS  Google Scholar 

  22. Oki K, Nagata E, Ishiko A, et al (2007) Novel mutation of the Notch3 gene in a Japanese patient with CADASIL. Eur J Neurol 14:464–466

    PubMed  CAS  Google Scholar 

  23. Oliveri RL, Muglia M, De Stefano N, et al (2001) A novel mutation in the Notch3 gene in an Italian family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: genetic and magnetic resonance spectroscopic findings. Arch Neurol 58:1418–1422

    PubMed  CAS  Google Scholar 

  24. Ragno M, Fabrizi GM, Cacchio G, et al (2006) Two novel Italian CADASIL families from Central Italy with mutation CGC-TGC at codon 1006 in the exon 19 Notch3 gene. Neurol Sci 27:252–256

    PubMed  CAS  Google Scholar 

  25. Arboleda-Velasquez JF, Rampal R, Fung E, et al (2005) CADASIL mutations impair Notch3 glycosylation by Fringe. Hum Mol Genet 14:1631–1639

    PubMed  CAS  Google Scholar 

  26. Kleinig TJ, Kimber T, Thompson PD (2007) Acute encephalopathy as the initial symptom of CADASIL. Intern Med J 37:786–787

    PubMed  CAS  Google Scholar 

  27. Schon F, Martin RJ, Prevett M, Clough C, Enevoldson TP, Markus HS (2003) “CADASIL coma”: an underdiagnosed acute encephalopathy. J Neurol Neurosurg Psychiatry 74: 249–252

    PubMed  CAS  Google Scholar 

  28. Dichgans M, Mayer M, Uttner I, et al (1998) The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol 44:731–739

    PubMed  CAS  Google Scholar 

  29. Nishio T, Arima K, Eto K, Ogawa M, Sunohara N (1997) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy – report of an autopsied Japanese case. Rinsho Shinkeigaku 37:910–916

    PubMed  CAS  Google Scholar 

  30. Williamson EE, Chukwudelunzu FE, Meschia JF, Witte RJ, Dickson DW, Cohen MD (1999) Distinguishing primary angiitis of the central nervous system from cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: the importance of family history. Arthritis Rheum 42:2243–2248

    PubMed  CAS  Google Scholar 

  31. Kumar SK, Mahr G (1997) CADASIL presenting as bipolar disorder. Psychosomatics 38:397–398

    PubMed  CAS  Google Scholar 

  32. Desmond DW, Moroney JT, Lynch T, Chan S, Chin SS, Mohr JP (1999) The natural history of CADASIL: a pooled analysis of previously published cases. Stroke 30:1230–1233

    PubMed  CAS  Google Scholar 

  33. Matsumoto H, Tsumoto M, Yamamoto T, et al (2005) A case of early stage CADASIL showing only dizziness and vertigo with a novel mutation of Notch 3 gene. Rinsho Shinkeigaku 45:27–31

    PubMed  Google Scholar 

  34. Lv H, Yao S, Zhang W, et al (2004) Clinical features in 4 Chinese families with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Beijing Da Xue Xue Bao 36:496–500

    PubMed  Google Scholar 

  35. Miranda M, Dichgans M, Slachevsky A, et al (2006) CADASIL presenting with a movement disorder: a clinical study of a Chilean kindred. Mov Disord 21:1008–1012

    PubMed  Google Scholar 

  36. Parisi V, Pierelli F, Fattapposta F, et al (2003) Early visual function impairment in CADASIL. Neurology 60:2008–2010

    PubMed  CAS  Google Scholar 

  37. Parisi V, Pierelli F, Malandrini A, et al (2000) Visual electrophysiological responses in subjects with cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Clin Neurophysiol 111: 1582–1588

    PubMed  CAS  Google Scholar 

  38. Mourad A, Levasseur M, Bousser MG, Chabriat H (2006) CADASIL with minimal symptoms after 60 years. Rev Neurol (Paris) 162:827–831

    CAS  Google Scholar 

  39. Trojano M, Paolicelli D (2001) The differential diagnosis of multiple sclerosis: classification and clinical features of relapsing and progressive neurological syndromes. Neurol Sci 22(Suppl 2):S98–S102

    PubMed  Google Scholar 

  40. Van Gerpen JA, Ahlskog JE, Petty GW (2003) Progressive supranuclear palsy phenotype ­secondary to CADASIL. Parkinsonism Relat Disord 9:367–369

    PubMed  CAS  Google Scholar 

  41. Pantoni L, Pescini F, Inzitari D, Dotti MT (2005) Postpartum psychiatric disturbances as an unrecognized onset of CADASIL. Acta Psychiatr Scand 112:241–242

    PubMed  Google Scholar 

  42. Otto V, Kaps M, Burgmann T, Kompf D (1997) CADASIL: 2 case reports of hereditary multi-infarct dementia. Fortschr Neurol Psychiatr 65:90–95

    PubMed  CAS  Google Scholar 

  43. Lagas PA, Juvonen V (2001) Schizophrenia in a patient with cerebral autosomally dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL disease). Nord J Psychiatry 55:41–42

    PubMed  CAS  Google Scholar 

  44. Phillips JS, King JA, Chandran S, Prinsley PR, Dick D (2005) Cerebral autosomal dominant arteriopathy with subcortical infarcts and ­leukoencephalopathy (CADASIL) presenting with sudden sensorineural hearing loss. J Laryngol Otol 119:148–151

    PubMed  Google Scholar 

  45. Wielaard R, Bornebroek M, Ophoff RA, et al (1995) A four-generation Dutch family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), linked to chromosome 19p13. Clin Neurol Neurosurg 97:307–313

    PubMed  CAS  Google Scholar 

  46. Opherk C, Peters N, Herzog J, Luedtke R, Dichgans M (2004) Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain 127:2533–2539

    PubMed  Google Scholar 

  47. Tuominen S, Juvonen V, Amberla K, et al (2001) Phenotype of a homozygous CADASIL patient in comparison to 9 age-matched heterozygous patients with the same R133C Notch3 mutation. Stroke 32:1767–1774

    PubMed  CAS  Google Scholar 

  48. Amberla K, Waljas M, Tuominen S, et al (2004) Insidious cognitive decline in CADASIL. Stroke 35:1598–1602

    PubMed  Google Scholar 

  49. Peters N, Herzog J, Opherk C, Dichgans M (2004) A two-year clinical follow-up study in 80 CADASIL subjects: progression patterns and implications for clinical trials. Stroke 35:1603–1608

    PubMed  Google Scholar 

  50. Opherk C, Peters N, Holtmannspotter M, Gschwendtner A, Muller-Myhsok B, Dichgans M (2006) Heritability of MRI lesion volume in CADASIL: evidence for genetic modifiers. Stroke 37:2684–2689

    PubMed  Google Scholar 

  51. Murakami T, Iwatsuki K, Hayashi T, et al (2001) Two Japanese CADASIL families with a R141C mutation in the Notch3 gene. Intern Med 40:1144–1148

    PubMed  CAS  Google Scholar 

  52. Pfefferkorn T, von Stuckrad-Barre S, Herzog J, Gasser T, Hamann GF, Dichgans M (2001) Reduced cerebrovascular CO(2) reactivity in CADASIL: A transcranial Doppler sonography study. Stroke 32:17–21

    PubMed  CAS  Google Scholar 

  53. Council of Biology (eds) (1994) Scientific style and format, 6th edn. Cambridge University Press, Cambridge, UK

    Google Scholar 

  54. Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284:770–776

    PubMed  CAS  Google Scholar 

  55. Bishop SA, Klein T, Arias AM, Couso JP (1999) Composite signalling from Serrate and Delta establishes leg segments in Drosophila through Notch. Development 126:2993–3003

    PubMed  CAS  Google Scholar 

  56. Kurata S, Go MJ, Artavanis-Tsakonas S, Gehring WJ (2000) Notch signaling and the determination of appendage identity. Proc Natl Acad Sci USA 97:2117–2122

    PubMed  CAS  Google Scholar 

  57. Justice NJ, Jan YN (2002) Variations on the Notch pathway in neural development. Curr Opin Neurobiol 12:64–70

    PubMed  CAS  Google Scholar 

  58. Costa RM, Drew C, Silva AJ (2005) Notch to remember. Trends Neurosci 28:429–435

    PubMed  CAS  Google Scholar 

  59. Lubman OY, Korolev SV, Kopan R (2004) Anchoring Notch genetics and biochemistry; structural analysis of the ankyrin domain sheds light on existing data. Mol Cell 13:619–626

    PubMed  CAS  Google Scholar 

  60. Barrick D, Kopan R (2006) The Notch transcription activation complex makes its move. Cell 124:883–885

    PubMed  CAS  Google Scholar 

  61. Whiteman P, Willis AC, Warner A, Brown J, Redfield C, Handford PA (2007) Cellular and molecular studies of Marfan syndrome mutations identify co-operative protein folding in the cbEGF12–13 region of fibrillin-1. Hum Mol Genet 16:907–918

    PubMed  CAS  Google Scholar 

  62. Okajima T, Irvine KD (2002) Regulation of Notch signaling by O-linked fucose. Cell 111:893–904

    PubMed  CAS  Google Scholar 

  63. Bruckner K, Perez L, Clausen H, Cohen S (2000) Glycosyltransferase activity of Fringe modulates Notch–Delta interactions. Nature 406:411–415

    PubMed  CAS  Google Scholar 

  64. Moloney DJ, Panin VM, Johnston SH, et al (2000) Fringe is a glycosyltransferase that modifies Notch. Nature 406:369–375

    PubMed  CAS  Google Scholar 

  65. Ju B-G, Jeong S, Bae E, et al (2000) Fringe forms a complex with Notch. Nature 405:191–195

    PubMed  CAS  Google Scholar 

  66. Irvine KD (1999) Fringe, Notch, and making developmental boundaries. Curr Opin Genet Dev 9:434–441

    PubMed  CAS  Google Scholar 

  67. Hicks C, Johnston SH, diSibio G, Collazo A, Vogt TF, Weinmaster G (2000) Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2. Nat Cell Biol 2:515–520

    PubMed  CAS  Google Scholar 

  68. Haines N, Irvine KD (2003) Glycosylation regulates Notch signalling. Nat Rev Mol Cell Biol 4:786–797

    PubMed  CAS  Google Scholar 

  69. Haltiwanger RS, Lowe JB (2004) Role of glycosylation in development. Annu Rev Biochem 73:491–537

    PubMed  CAS  Google Scholar 

  70. Chitnis A (2006) Why Is Delta endocytosis required for effective activation of Notch? Dev Dyn 235:886–894

    PubMed  CAS  Google Scholar 

  71. Le Borgne R, Bardin A, Schweisguth F (2005) The roles of receptor and ligand endocytosis in regulating Notch signaling. Development 132:1751–1762

    PubMed  CAS  Google Scholar 

  72. Lai EC, Roegiers F, Qin X, Jan YN, Rubin GM (2005) The ubiquitin ligase Drosophila Mind bomb promotes Notch signaling by regulating the localization and activity of Serrate and Delta. Development 132:2319–2332

    PubMed  CAS  Google Scholar 

  73. Parks AL, Klueg KM, Stout JR, Muskavitch MAT (2000) Ligand endocytosis drives receptor dissociation and activation in the Notch pathway. Development 127:1373–1385

    PubMed  CAS  Google Scholar 

  74. Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7:678–689

    PubMed  CAS  Google Scholar 

  75. Hsieh JJ-D, Henkel T, Salmon P, Robey E, Peterson MG, Hayward SD (1996) Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2. Mol Cell Biol 16:952–959

    PubMed  CAS  Google Scholar 

  76. Bardot B, Mok LP, Thayer T, Ahimou F, Wesley C (2005) The Notch amino terminus regulates protein levels and Delta-induced clustering of Drosophila Notch receptors. Exp Cell Res 304:202–223

    PubMed  CAS  Google Scholar 

  77. Schweisguth F (2004) Notch signaling activity. Curr Biol 14:R129–R138

    PubMed  CAS  Google Scholar 

  78. Siekmann AF, Covassin L, Lawson ND (2008) Modulation of VEGF signalling output by the Notch pathway. Bioessays 30:303–313

    PubMed  CAS  Google Scholar 

  79. Lawson ND, Vogel AM, Weinstein BM (2002) sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev Cell 3:127–136

    PubMed  CAS  Google Scholar 

  80. Weinstein BM, Lawson ND (2002) Arteries, veins, Notch, and VEGF. Cold Spring Harb Symp Quant Biol 67:155–162

    PubMed  CAS  Google Scholar 

  81. Siekmann AF, Lawson ND (2007) Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature 445:781–784

    PubMed  CAS  Google Scholar 

  82. Lawson ND, Scheer N, Pham VN, et al (2001) Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development 128:3675–3683

    PubMed  CAS  Google Scholar 

  83. Villa N, Walker L, Lindsell CE, Gasson J, Iruela-Arispe ML, Weinmaster G (2001) Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech Dev 108:161–164

    PubMed  CAS  Google Scholar 

  84. Campos AH, Wang W, Pollman MJ, Gibbons GH (2002) Determinants of Notch-3 receptor expression and signaling in vascular smooth muscle cells: implications in cell-cycle regulation. Circ Res 91:999–1006

    PubMed  CAS  Google Scholar 

  85. Iso T, Hamamori Y, Kedes L (2003) Notch signaling in vascular development. Arterioscler Thromb Vasc Biol 23:543–553

    PubMed  CAS  Google Scholar 

  86. Ruchoux MM, Domenga V, Brulin P, et al (2003) Transgenic mice expressing mutant Notch3 develop vascular alterations characteristic of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Am J Pathol 162:329–342

    PubMed  CAS  Google Scholar 

  87. Gridley T (2007) Notch signaling in vascular development and physiology. Development 134:2709–2718

    PubMed  CAS  Google Scholar 

  88. Owens GK, Kumar MS, Wamhoff BR (2004) Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev 84:767–801

    PubMed  CAS  Google Scholar 

  89. Huppert SS, Le A, Schroeter EH, et al (2000) Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1. Nature 405:966–970

    PubMed  CAS  Google Scholar 

  90. Krebs LT, Xue Y, Norton CR, et al (2000) Notch signaling is essential for vascular morphogenesis in mice. Genes Dev 14:1343–1352

    PubMed  CAS  Google Scholar 

  91. Limbourg FP, Takeshita K, Radtke F, Bronson RT, Chin MT, Liao JK (2005) Essential role of endothelial Notch1 in angiogenesis. Circulation 111:1826–1832

    PubMed  CAS  Google Scholar 

  92. Carlson TR, Yan Y, Wu X, et al (2005) Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice. Proc Natl Acad Sci USA 102:9884–9889

    PubMed  CAS  Google Scholar 

  93. Uyttendaele H, Ho J, Rossant J, Kitajewski J (2001) Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium. Proc Natl Acad Sci USA 98:5643–5648

    PubMed  CAS  Google Scholar 

  94. Joutel A, Andreux F, Gaulis S, et al (2000) The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. J Clin Invest 105:597–605

    PubMed  CAS  Google Scholar 

  95. Domenga V, Fardoux P, Lacombe P, et al (2004) Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev 18:2730–2735

    PubMed  CAS  Google Scholar 

  96. Krebs LT, Xue Y, Norton CR, et al (2003) Characterization of Notch3-deficient mice: normal embryonic development and absence of genetic interactions with a Notch1 mutation. Genesis 37:139–143

    PubMed  CAS  Google Scholar 

  97. Mitchell KJ, Pinson KI, Kelly OG, et al (2001) Functional analysis of secreted and transmembrane proteins critical to mouse development. Nat Genet 28:241–249

    PubMed  CAS  Google Scholar 

  98. Kitamoto T, Takahashi K, Takimoto H, et al (2005) Functional redundancy of the Notch gene family during mouse embryogenesis: analysis of Notch gene expression in Notch3-deficient mice. Biochem Biophys Res Commun 331:1154–1162

    PubMed  CAS  Google Scholar 

  99. Monet M, Domenga V, Lemaire B, et al (2007) The archetypal R90C CADASIL-NOTCH3 mutation retains NOTCH3 function in vivo. Hum Mol Genet 16:982–992

    PubMed  CAS  Google Scholar 

  100. Moessler H, Mericskay M, Li Z, Nagl S, Paulin D, Small JV (1996) The SM 22 promoter directs tissue-specific expression in arterial but not in venous or visceral smooth muscle cells in transgenic mice. Development 122:2415–2425

    PubMed  CAS  Google Scholar 

  101. Adriani W, Macrì S, Pacifici R, Laviola G (2002) Peculiar vulnerability to nicotine oral self-administration in mice during early adolescence. Neuropsychopharmacology 27:212–224

    PubMed  CAS  Google Scholar 

  102. Sakata Y, Xiang F, Chen Z, et al (2004) Transcription factor CHF1/Hey2 regulates neointimal formation in vivo and vascular smooth muscle proliferation and migration in vitro. Arterioscler Thromb Vasc Biol 24:2069–2074

    PubMed  CAS  Google Scholar 

  103. Sweeney C, Morrow D, Birney YA, et al (2004) Notch 1 and 3 receptor signaling modulates vascular smooth muscle cell growth, apoptosis, and migration via a CBF-1/RBP-Jk dependent pathway. FASEB J 18:1421–1423

    PubMed  CAS  Google Scholar 

  104. Doi H, Iso T, Yamazaki M, et al (2005) HERP1 inhibits myocardin-induced vascular smooth muscle cell differentiation by interfering with SRF binding to CArG box. Arterioscler Thromb Vasc Biol 25:2328–2334

    PubMed  CAS  Google Scholar 

  105. Wang W, Campos AH, Prince CZ, Mou Y, Pollman MJ (2002) Coordinate Notch3-hairy-related transcription factor pathway regulation in response to arterial injury. Mediator role of platelet-derived growth factor and ERK. J Biol Chem 277:23165–23171

    PubMed  CAS  Google Scholar 

  106. Lindner V, Booth C, Prudovsky I, Small D, Maciag T, Liaw L (2001) Members of the Jagged/Notch gene families are expressed in injured arteries and regulate cell phenotype via alterations in cell matrix and cell-cell interaction. Am J Pathol 159:875–883

    PubMed  CAS  Google Scholar 

  107. Morrow D, Sweeney C, Birney YA, et al (2005) Cyclic strain inhibits Notch receptor signaling in vascular smooth muscle cells in vitro. Circ Res 96:567–575

    PubMed  CAS  Google Scholar 

  108. Morrow D, Scheller A, Birney YA, et al (2005) Notch-mediated CBF-1/RBP-J {kappa} -dependent regulation of human vascular smooth muscle cell phenotype in vitro. Am J Physiol Cell Physiol 289:C1188–C1196

    PubMed  CAS  Google Scholar 

  109. Nakamura T, Watanabe H, Hirayama M, et al (2005) CADASIL with NOTCH3 S180C presenting anticipation of onset age and hallucinations. J Neurol Sci 238:87–91

    PubMed  CAS  Google Scholar 

  110. Dichgans M, Ludwig H, Muller-Hocker J, Messerschmidt A, Gasser T (2000) Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains. Eur J Hum Genet 8:280–285

    PubMed  CAS  Google Scholar 

  111. Ishida C, Sakajiri K, Yoshita M, Joutel A, Cave-Riant F, Yamada M (2006) CADASIL with a novel mutation in exon 7 of NOTCH3 (C388Y). Intern Med 45:981–985

    PubMed  Google Scholar 

  112. Joutel A, Dodick DD, Parisi JE, Cecillon M, Tournier-Lasserve E, Bousser MG (2000) De novo mutation in the Notch3 gene causing CADASIL. Ann Neurol 47:388–391

    PubMed  CAS  Google Scholar 

  113. Kim Y, Choi EJ, Choi CG, et al (2006) Characteristics of CADASIL in Korea: a novel cysteine-sparing Notch3 mutation. Neurology 66:1511–1516

    PubMed  CAS  Google Scholar 

  114. Kotani N, Hara H, Fujimura H, Miyashita T, Miyaguchi K, Tabira T (2004) A case of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and lekoencephalopathy) with Notch 3 (Arg169Cys) mutation and typical granular osmiophilic materials in peripheral small arteries. Rinsho Shinkeigaku 44:274–279

    PubMed  Google Scholar 

  115. Kotorii S, Takahashi K, Kamimura K, et al (2001) Mutations of the notch3 gene in non-caucasian patients with suspected CADASIL syndrome. Dement Geriatr Cogn Disord 12:185–193

    PubMed  CAS  Google Scholar 

  116. Posada IJ, Garcia-Morales I, Martinez MA, Hoenicka J, Bermejo F (2003) CADASIL: a case with clinical, radiological, histological and genetic diagnoses. Neurologia 18:229–233

    PubMed  CAS  Google Scholar 

  117. Fouillade C, Chabriat H, Riant F, et al (2008) Activating NOTCH3 mutation in a patient with small-vessel-disease of the brain. Hum Mutat 29:452

    PubMed  Google Scholar 

  118. Mazzei R, Conforti FL, Lanza PL, et al (2004) A novel Notch3 gene mutation not involving a cysteine residue in an Italian family with CADASIL. Neurology 63:561–564

    PubMed  CAS  Google Scholar 

  119. Hagel C, Groden C, Niemeyer R, Stavrou D, Colmant HJ (2004) Subcortical angiopathic encephalopathy in a German kindred suggests an autosomal dominant disorder ­distinct from CADASIL. Acta Neuropathol 108:231–240

    PubMed  CAS  Google Scholar 

  120. Ito D, Tanahashi N, Murata M, et al (2002) Notch3 gene polymorphism and ischaemic cerebrovascular disease. J Neurol Neurosurg Psychiatry 72:382–384

    PubMed  CAS  Google Scholar 

  121. Donahue CP, Kosik KS (2004) Distribution pattern of Notch3 mutations suggests a gain-of-function mechanism for CADASIL. Genomics 83:59–65

    PubMed  CAS  Google Scholar 

  122. Ruchoux MM, Maurage CA (1997) CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neuropathol Exp Neurol 56:947–964

    PubMed  CAS  Google Scholar 

  123. Ishiko A, Shimizu A, Nagata E, Takahashi K, Tabira T, Suzuki N (2006) Notch3 ectodomain is a major component of granular osmiophilic material (GOM) in CADASIL. Acta Neuropathol 112:333–339

    PubMed  CAS  Google Scholar 

  124. Shifley ET, Vanhorn KM, Perez-Balaguer A, Franklin JD, Weinstein M, Cole SE (2008) Oscillatory lunatic fringe activity is crucial for segmentation of the anterior but not posterior skeleton. Development 135:899–908

    PubMed  CAS  Google Scholar 

  125. Lindsley DL, Zimm GG (1992) The genome of Drosophila melanogaster. Academic Press, New York

    Google Scholar 

  126. Brennan K, Tateson R, Lieber T, Couso JP, Zecchini V, Arias AM (1999) The Abruptex mutations of Notch disrupt the establishment of proneural clusters in Drosophila. Dev Biol 216:230–242

    PubMed  CAS  Google Scholar 

  127. Muller HJ (1962) Studies in genetics: the selected papers of H. J. Muller. Indiana University Press, Bloomington, IN

    Google Scholar 

  128. Kelley MR, Kidd S, Deutsch WA, Young MW (1987) Mutations altering the structure of epidermal growth factor-like coding seque‑nces at the Drosophila Notch locus. Cell 51:539–548

    PubMed  CAS  Google Scholar 

  129. Xu T, Rebay I, Fleming RJ, Scottgale NT, Artavanis-Tsakonas S (1990) The Notch locus and the genetic circuitry involved in early Drosophila neurogenesis. Genes Dev 4:464–475

    PubMed  CAS  Google Scholar 

  130. Kidd S, Lieber T (2002) Furin cleavage is not a requirement for Drosophila Notch function. Mech Dev 115:41–51

    PubMed  CAS  Google Scholar 

  131. Joutel A, Monet M, Domenga V, Riant F, Tournier-Lasserve E (2004) Pathogenic mutations associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy differently affect Jagged1 binding and Notch3 activity via the RBP/JK signaling Pathway. Am J Hum Genet 74:338–347

    PubMed  CAS  Google Scholar 

  132. Low WC, Santa Y, Takahashi K, Tabira T, Kalaria RN (2006) CADASIL-causing mutations do not alter Notch3 receptor processing and activation. Neuroreport 17:945–949

    PubMed  CAS  Google Scholar 

  133. Haritunians T, Chow T, De Lange RP, et al (2005) Functional analysis of a recurrent missense mutation in Notch3 in CADASIL. J Neurol Neurosurg Psychiatry 76: 1242–1248

    PubMed  CAS  Google Scholar 

  134. Karlstrom H, Beatus P, Dannaeus K, Chapman G, Lendahl U, Lundkvist J (2002) A CADASIL-mutated Notch 3 receptor exhibits impaired intracellular trafficking and maturation but normal ligand-induced signaling. Proc Natl Acad Sci USA 99:17119–17124

    PubMed  CAS  Google Scholar 

  135. Fryxell KJ (1996) The coevolution of gene family trees. Trends Genet 12:364–369

    PubMed  CAS  Google Scholar 

  136. Lacombe P, Oligo C, Domenga V, Tournier-Lasserve E, Joutel A (2005) Impaired cerebral vasoreactivity in a transgenic mouse model of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy arteriopathy. Stroke 36: 1053–1058

    PubMed  Google Scholar 

  137. Dubroca C, Lacombe P, Domenga V, et al (2005) Impaired vascular mechanotransduction in a transgenic mouse model of CADASIL arteriopathy. Stroke 36:113–117

    PubMed  Google Scholar 

  138. Lundkvist J, Zhu S, Hansson EM, et al (2005) Mice carrying a R142C Notch 3 knock-in mutation do not develop a CADASIL-like phenotype. Genesis 41:13–22

    PubMed  CAS  Google Scholar 

  139. Schrijver I, Liu W, Brenn T, Furthmayr H, Francke U (1999) Cysteine substitutions in epidermal growth factor–like domains of Fibrillin-1: distinct effects on biochemical and clinical phenotypes. Am J Hum Genet 65:1007–1020

    PubMed  CAS  Google Scholar 

  140. Dietz HC, Saraiva JM, Pyeritz RE, Cutting GR, Francomano CA (1992) Clustering of fibrillin (FBN1) missense mutations in Marfan syndrome patients at cysteine residues in EGF-like domains. Hum Mutat 1:366–374

    PubMed  CAS  Google Scholar 

  141. Whiteman P, Handford PA (2003) Defective secretion of recombinant fragments of ­fibrillin-1: implications of protein misfolding for the pathogenesis of Marfan syndrome and related disorders. Hum Mol Genet 12:727–737

    PubMed  CAS  Google Scholar 

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Acknowledgments

Scientific interest in CADASIL has grown in recent years to the point where it is no longer possible to cite every scientific paper in this area. I apologize in advance to anyone whose contributions may have been inadvertently omitted. I also thank the Editors for their patience and support.

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Authors and Affiliations

  1. Center for Biomedical Genomics & Informatics, Department of Molecular & Microbiology, George Mason University, Manassas, VA, USA

    Karl J. Fryxell

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  1. Karl J. Fryxell
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Editors and Affiliations

  1. Institute Born-Bunge, Lab of Neurochemistry & Behaviour, University of Antwerp, Universiteitsplein 1, Wilrijk, 2610, Belgium

    Peter Paul De Deyn

  2. Institute Born-Bunge, Lab of Neurochemistry & Behaviour, University of Antwerp, Universiteitsplein 1, Wilrijk, 2610, Belgium

    Debby Van Dam

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Fryxell, K.J. (2011). CADASIL: Molecular Mechanisms and Animal Models. In: De Deyn, P., Van Dam, D. (eds) Animal Models of Dementia. Neuromethods, vol 48. Humana Press. https://doi.org/10.1007/978-1-60761-898-0_29

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  • DOI: https://doi.org/10.1007/978-1-60761-898-0_29

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  • Print ISBN: 978-1-60761-897-3

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