Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease

Area of Science:

• Neuroscience
• Genetics
• Vascular Biology

Background:

• Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a common monogenic cause of ischemic stroke and vascular dementia.
• CADASIL is linked to mutations in the Notch 3 receptor, leading to vascular smooth muscle cell degeneration and granular osmiophilic material (GOM) accumulation.
• The precise functional impact of Notch 3 mutations and their link to disease pathogenesis remain unclear.

Purpose of the Study:

• To elucidate the functional consequences of specific Notch 3 mutations (C455R and R1031C) in CADASIL.
• To investigate the mechanistic link between Notch 3 dysfunction, small-vessel disease, and GOM formation.
• To identify molecular components of GOM in human CADASIL pathology.

Main Methods:

• Hemodynamic analyses in transgenic mouse models harboring CADASIL-associated Notch 3 mutations.
• Receptor activity assays in cell culture to assess Notch 3 function.
• Proteomic analysis of postmortem human brain vessels from CADASIL patients.

Main Results:

• The studied Notch 3 mutations (C455R, R1031C) result in distinct hypomorphic activity states of the receptor.
• Transgenic mouse models exhibited phenotypes mirroring human CADASIL, including GOM deposition and age-dependent pathologies.
• Proteomic analysis identified clusterin and collagen 18 α1/endostatin as key components of GOM in human brain vessels.

Conclusions:

• CADASIL pathophysiology involves hypomorphic Notch 3 function in vascular smooth muscle cells, contributing to ischemic cerebral small-vessel disease.
• The accumulation of clusterin and collagen 18 α1/endostatin is implicated in the vascular pathology of CADASIL.
• These findings establish a link between impaired Notch signaling and a prevalent human cerebrovascular condition.