The NOTCH3ECD cascade hypothesis of cerebral autosomal‐dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease

Background Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, with an autosomal dominant mode of transmission, is an archetypal small vessel disease of the brain that has emerged as the most common heritable cause of stroke and vascular dementia worldwide. Aims and methods Here we review the current knowledge on the pathogenesis of this disease. Results The disease is caused by highly stereotyped missense mutations that alter the number of cysteine residues in the extracellular domain of NOTCH3, a transmembrane receptor that undergoes a series of proteolytic cleavages on ligand binding that release the extracellular domain, and ultimately enable the intracellular domain to translocate to the nucleus, where it acts as a transcriptional activator. NOTCH3 is predominantly expressed in vascular smooth muscle cells, and is critical for the structure and function of small vessels of the brain. Mutations differentially affect NOTCH3 transcriptional activity; however, it is still debated whether a reduction in NOTCH3 activity might contribute to the disease process. In contrast, all disease associated NOTCH3 mutations are associated with an early accumulation, aggregation and deposition of the extracellular domain at the plasma membrane of smooth muscle cells, in extracellular deposits called granular osmiophilic material. Importantly, recent work identified a novel mechanism in which excess of the extracellular domain of NOTCH3 promotes the abnormal recruitment of proteins of the extracellular matrix that might cause multifactorial toxicity in the brain vessels. Conclusion Recent studies lend support to a NOTCH3ECD cascade hypothesis in in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy that posits that the deposition of NOTCH3 extracellular domain in the brain vessels initiates a sequence of events that ultimately lead to stroke and dementia.