REVIEW Overlapping Protein Accumulation Pro fi les of CADASIL and CAA Is There a Common Mechanism Driving Cerebral Small-Vessel Disease?

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and cerebral amyloid angiopathy (CAA) are two distinct vascular angiopathies that share several similarities in clinical presentation and vascular pathology. Given the clinical and pathologic overlap, the molecular overlap between CADASIL and CAAwas explored. CADASIL and CAA proteinpro fi lesfrom recently published proteomics-based and immuno-based studies were compared to investigate the potential for shared disease mechanisms. A comparison of affected proteins in each disease highlighted 19 proteins that are regulated in both CADASIL and CAA. Functional analysis of the shared proteins predicts signi fi cant interaction between them and suggests that most enriched proteins play roles in extracellular matrix structure and remodeling. Proposed models to explain the observed enrichment of extracellular matrix proteins include both increased protein secretion and decreased protein turnover by sequestration of chaperonesandproteasesorformationofstableproteincomplexes.Single-cellRNAsequencingofvascularcellsinmicesuggestedthatthevastmajorityofthegenesaccountingfortheoverlappedproteinsbetween CADASIL and CAA are expressed by fi broblasts. Thus, our current understanding of the molecular pro fi les of CADASIL and CAA appears to support potential for common mechanisms underlying the two disorders.