Pathogenesis of CADASIL: transgenic and knock-out mice to probe function and dysfunction of the mutated gene, Notch3, in the cerebrovasculature

Small vessel diseases (SVDs) of the brain are the leading cause of vascular cognitive impairment and a major contributor to stroke in the human adult, however, their pathogenesis is poorly understood. Dominant mutations in NOTCH3 cause CADASIL, one of the most prevalent inherited cerebral SVDs. The disease gene encodes a transmembrane receptor primarily expressed in smooth muscle cells of small arteries and pericytes of brain capillaries. Pathogenic mutations alter the number of cysteine residues in the extracellular domain of NOTCH3, leading to its abnormal accumulation in the vessels of patients. Mice lacking NOTCH3 have revealed a critical role for NOTCH3 in the elaboration of small arteries. Despite being incomplete disease models, transgenic mice expressing CADASIL-associated NOTCH3 mutations, have provided important insights into specific aspects of CADASIL pathogenesis, including the functional significance of disease-linked mutations and the earliest pathological events that initiate brain lesions. In this paper, I provide a critical overview of these studies. Moreover, I discuss future directions and further work that needs to be done.