Fig. 2. Pathogenesis of CADASIL-causing NOTCH3 mutations. There is currently still no consensus on the pathogenesis of CADASIL. Major hypotheses proposed so far are aberrant NOTCH3 signaling, toxic NOTCH3 extracellular domain (NECD) aggregation, and matrisomes. ECM, extracellular matrix; ER, endoplasmic reticulum; GOM, granular osmiophilic material; IPAD, intramural periarterial drainage; NEXT, Notch3 extracellular truncation; NICD, Notch3 intracellular domain.