The role of NOTCH3 in CADASIL pathogenesis: insights into novel therapies

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenetic hereditary small-vessel disorder characterised by recurrent subcortical ischemic strokes, cognitive deterioration, and other neurological symptoms. Single nucleotide mutations within the NOTCH3 gene can impair NOTCH3 processing and/or signalling, resulting in the accumulation of granular osmiophilic material (GOM) in blood vessel walls, and consequently CADASIL. Despite its significant clinical impact, there is currently no definitive treatment for CADASIL. This review provides a comprehensive analysis of the pathophysiological mechanisms underlying CADASIL, focusing on NOTCH3 mutations and their effects on protein processing and signalling. The review proposes a hypothesis that explains how NOTCH3 mutations may alter the signalling process and result in GOMs. Additionally, the review explores published therapy strategies aimed at restoring normal NOTCH3 function.