CADASIL associated Notch3 mutations have differential effects both on ligand binding and ligand-induced Notch3 receptor signaling

Mutations in the Notch3 gene are the cause of CADASIL, a hereditary microangiopathy leading to stroke and vascular dementia. Typical mutations lead to an odd number of cysteine residues within an epidermal-growth-factor (EGF-) repeat in the extracellular domain of the Notch3 transmembrane receptor. In CADASIL, the extracellular domain of Notch3 (N3ECD) is deposited in the vicinity of vascular smooth muscle cells (VSMC), which have been shown to degenerate in patients. However, the mechanisms underlying VSMC degeneration and N3ECD accumulation are still unknown. Here we investigated the consequences of three path…