Signaling pathways and molecular mechanisms involved in the onset and progression of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL); a focus on Notch3 signaling.
Level 5 - mechanism / opinion, no new human data
Narrative review of molecular mechanisms without systematic synthesis or primary human data.
PubMed 40301727 · doi:10.1186/s10194-025-02025-z
What was done
The authors synthesized published literature on the molecular mechanisms and signaling pathways involved in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), focusing on NOTCH3 signaling and related pathways such as transforming growth factor beta (TGF-β).
What was found
The abstract reports qualitative mechanistic descriptions and provides no quantitative data. It outlines that pathogenic NOTCH3 mutations alter cysteine residue counts in the extracellular domain, leading to granular osmiophilic material accumulation in cerebral small-artery smooth muscle cells and capillary pericytes, and notes possible involvement of TGF-β signaling.
Why it matters
Understanding the molecular cascade initiated by NOTCH3 mutations helps clarify the biology of hereditary cerebral small-vessel disease and highlights potential molecular targets for future CADASIL therapeutics.
Limits
As a narrative review, it lacks a systematic search strategy, formal study selection criteria, and risk-of-bias evaluation. No primary clinical or experimental data are presented, and therapeutic implications remain theoretical.
Cited by
- supports CADASIL involves NOTCH3 protein aggregates in pericytes and vascular smooth muscle cells, leading to severe white matter disease and cognitive decline beginning around age 30 to 40.