Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leucoencephalopathy (CADASIL)
https://biosignaling.biomedcentral.com/articles/10.1186/s12964-025-02362-1
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare inherited form of small vessel disease that causes strokes, migraines, and dementia. It is a result of mutations in the gene NOTCH3, which provides instructions for a receptor protein found on the surface of blood vessel cells. In CADASIL, fragments of the outer part of this protein, known as the extracellular domain (ECD), accumulate around vessels and are thought to damage them over time. In this study, researchers investigated how NOTCH3 and several CADASIL-associated mutations behave inside cells. They used fluorescent tags and advanced imaging to follow the protein’s movement and processing. They discovered that NOTCH3 reaches the cell surface normally but is then brought inside through endocytosis (a process where substances are brought into a cell). Inside the cell, the ECD separates from the rest of the protein within compartments known as endosomes which sort and process substances in cells. This shedding process appears to be a key step in how NOTCH3 becomes active. Importantly, not all mutations acted the same way. One common mutation, R90C, showed unusually high activity and used a different activation route that did not rely on the usual enzymes. This suggests that CADASIL mutations can cause disease through distinct mechanisms rather than a single pathway. These findings reveal new insights into how NOTCH3 functions and why some CADASIL mutations are more damaging. Understanding these mechanisms could help researchers design targeted treatments to prevent vessel damage and slow disease progression.