CADASIL: Notch Signaling Defect Or Protein Accumulation Problem?
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CADASIL: Notch signaling defect or protein accumulation problem? Nancy B. Spinner J Clin Invest. 2000;105(5):561-562. https://doi.org/10.1172/JCI9511. Commentary When studies of the genetic etiology of human disease intersect with those of basic mechanisms in developmental biology, our understanding of normal and abnormal development is increased, and the knowledge gained enriches the work of both human geneticists and basic scientists. Such is the case with the work of A. Joutel et al. (1), who have previously demonstrated that mutations in the Notch3 gene are the cause of the autosomal dominant disorder CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). CADASIL is an adult-onset neurologic disorder (average age of onset is 45 years) characterized by recurrent strokes and dementia. Through positional cloning, Notch3 was found to be the gene responsible for the disorder (1), and mutations have been demonstrated in more than 90% of CADASIL patients (1, 2). The highly conserved Notch signaling pathway was originally identified and studied in the fruit fly Drosophila melanogaster. The name “Notch” derives from the characteristic notched wing found in flies carrying only 1 functioning copy of the gene. Homozygous Notch mutations are lethal, and affected embyros have severe abnormalities, including an excess of neural cells (3). A large body of work in the fruit fly, the nematode Caenorhabditis elegans, and more recently in vertebrates has revealed that this pathway plays a prominent role in development by contributing to the determination of […] Find the latest version: https://jci.me/9511/pdf CADASIL: Notch signaling defect or protein Commentary accumulation problem? See related article, pages 597–605. Nancy B. Spinner Divisions of Human Genetics and Clinical Laboratories, and Department of Pediatrics, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA. Phone: (215) 590-4177; Fax: (215) 590-3850; E-mail: [email protected]. When studies of the genetic etiology of in 3 translocations in patients with T- In this issue of the JCI, A. Joutel et al. human disease intersect with those of cell neoplasms (4). At least 4 ligands for present studies on the expression and basic mechanisms in developmental Notch are known in humans (Jagged1, subcellular localization of Notch3 in biology, our understanding of normal Jagged2, Delta-like1, and Delta-like3); normal brains and in the brains of indi- and abnormal development is to date, only the Jagged1 gene has been viduals with CADASIL. In healthy indi- increased, and the knowledge gained associated with human disease. In the viduals as well as in CADASIL patients, enriches the work of both human mouse, mutations in Delta-like3 cause Notch3 is present in the smooth mus- geneticists and basic scientists. Such is the Pudgy phenotype, which is charac- cle cells in the cerebral vasculature, but the case with the work of A. Joutel et al. terized by severe vertebral and rib defor- in the CADASIL patients, the extracel- (1), who have previously demonstrated mities (5). Mice homozygous for muta- lular domain of the receptor accumu- that mutations in the Notch3 gene are tions in Jagged2 die in utero, secondary lates abnormally (12). Evidence from the cause of the autosomal dominant to severe defects in craniofacial mor- Drosophila has demonstrated that disorder CADASIL (cerebral autosomal phogenesis, and also display defects of Notch1 reaches the cell surface in 2 dominant arteriopathy with subcortical the limbs and thymus (6). Mutations in parts. The nascent Notch1 peptide is infarcts and leukoencephalopathy). human Jagged1 underlie Alagille syn- cleaved into 2 domains in the trans- CADASIL is an adult-onset neurologic drome, a dominant congenital disorder Golgi network, and appears on the cell disorder (average age of onset is 45 associated with abnormalities of the surface as an extracellular protein com- years) characterized by recurrent liver, heart, skeleton, eye, and face (7, 8). plexed with an integral membrane pro- strokes and dementia. Through posi- In general, the nature of the mutations tional cloning, Notch3 was found to be in this disorder suggests that haploin- the gene responsible for the disorder sufficiency for Jagged1 causes disease, (1), and mutations have been demon- because most of the mutations truncate strated in more than 90% of CADASIL the Jagged1 open reading frame or delete Perhaps mutant Notch3 patients (1, 2). The highly conserved the gene entirely (9, 10). molecules sop up ligand Notch signaling pathway was original- The adult-onset character of without transmitting a signal, ly identified and studied in the fruit fly CADASIL contrasts with the develop- Drosophila melanogaster. The name mental abnormalities associated with dominantly inhibiting the “Notch” derives from the characteristic mutations in the other Notch signaling normal pathway. notched wing found in flies carrying pathway genes studied to date. The only 1 functioning copy of the gene. Notch3 mutations seen in patients with Homozygous Notch mutations are CADASIL are transmitted in a domi- tein that consists of the original trans- lethal, and affected embyros have severe nant fashion, but unlike Alagille syn- membrane segment and the abnormalities, including an excess of drome, CADASIL does not seem to arise intracellular domain (3). On stimula- neural cells (3). A large body of work in from haploinsufficiency. Most tion of the receptor by ligand, the intra- the fruit fly, the nematode Caenorhabdi- CADASIL patients have a missense cellular domain translocates into the tis elegans, and more recently in verte- mutation leading to addition or loss of nucleus, where it mediates downstream brates has revealed that this pathway a cysteine residue within 1 of the 34 effects in conjunction with intercellu- plays a prominent role in development EGF-like repeats (2) in the Notch3 pro- lar regulatory proteins (13). Levels of by contributing to the determination of tein. The EGF-like repeats consist of the intracellular domain of Notch3 are cell fate in many different tissues (3). 40–50 amino acids, and are found in a not elevated in CADASIL tissue (12). The study of the effects of mutations large number of extracellular proteins Presumably, during or after normal in members of this pathway and their with diverse functions. These invariably Notch signaling, the extracellular pro- roles in human disease is in its infancy. contain 6 conserved cysteine residues teins must be cleared from the cell Of the 4 human Notch genes (Notch1, 2, that form 3 disulfide bonds, which are membrane. Little is known about this 3, and 4), only Notch1 and Notch3 have believed to be important for protein sta- process in vertebrates, but in Drosophi- been implicated in human disease, and bilization and protein-protein interac- la, normal Notch signaling requires the only Notch3 has been associated with tion (11). Notch3 mutations in CADASIL functioning of the protein dynamin, germline mutations that cause inherit- patients all lead to an odd number of which is required for endocytosis of the ed disease. Notch1 (previously called cysteine residues in the affected EGF receptor (14). TAN-1, for translocation-associated domain, which would be predicted to Is CADASIL caused by a defect in Notch1) has been shown to be involved disrupt the canonical disulfide pairing. Notch signaling, or by an inability to The Journal of Clinical Investigation | March 2000 | Volume 105 | Number 5 561 effectively remove the extracellular Alzheimer’s disease (AD1), missense phoblastic neoplasms. Cell. 66:649–661. domain from the membrane? Do the mutations in the amyloid precursor 5. Kusumi, K., et al. 1998. The mouse pudgy muta- tion disrupts Delta homologue Dll3 and initia- missense mutations seen in CADASIL protein lead to its abnormal accumula- tion of early somite boundaries. Nat. Genet. patients block endocytosis of the Notch tion (16). Furthermore, in some fami- 19:274–278. receptor? The common features of the lies, Parkinson’s disease is associated 6. Jiang, R., et al. 1999. Defects in limb, craniofacial, α and thymic development in Jagged2 mutant CADASIL mutations and the fact that with missense mutations in -synucle- mice. Genes Dev. 12:1046–1057. none of the patients studied to date car- in and the presence of proteinaceous 7. Li, L., et al. 1997. Alagille syndrome is caused by ries an obvious null allele of Notch3 sug- cytoplasmic inclusions known as Lewy mutations in human Jagged1, which encodes a lig- and for Notch1. Nat. Genet. 16:243–251. gest that this disease does not arise sim- bodies (17). Huntington’s disease arises 8. Oda, T., et al. 1997. Mutations in the human ply from loss of Notch signaling. from an expansion of a nucleotide Jagged1 gene are responsible for Alagille syn- Further experiments are needed to triplet repeat at the DNA level, which drome. Nat. Genet. 16:235–242. determine if the mutant Notch3 mole- results in synthesis of huntingtin pro- 9. Krantz, I.D., et al. 1998. Spectrum and frequency of Jagged1 (JAG1) mutations in Alagille syn- cule can respond to ligand and transmit tein containing an abnormal polyglut- drome patients and their families. Am. J. Hum. a signal. This will require analysis of amine tract. The mutant huntingtin Genet. 62:1361–1369. these mutants in an in vitro assay molecule also forms protein aggregates 10. Crosnier, C., et al. 1999. Analysis of mutations of the Jagged1 gene in patients with Alagille syn- designed to measure downstream sig- (18), although the role of these aggre- drome: evidence for most cases being sporadic. naling of stimulated Notch3, which is gates in pathogenesis is hotly debated. Gastroenterology. 116:1141–1148. not currently available. Even if the Multiple lines of evidence suggest 11. Campbell, I.D., and Bork, P. 1993. Epidermal growth factor-like module. Curr. Opin. Struct. Biol. mutant molecules prove inactive in that Notch signaling is important in 3:385–392.