Mice carrying a R142C Notch 3 knock-in mutation do not develop a CADASIL-like phenotype

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a genetic vascular dementia.
• It is caused by mutations in the human NOTCH3 gene, including missense mutations, deletions, and splice site alterations.

Purpose of the Study:

• To generate a mouse knockin model for the prevalent CADASIL R141C mutation in the NOTCH3 gene.
• To investigate the in vivo phenotype of this specific CADASIL mutation in a mammalian model.

Main Methods:

• Generation of a mouse model with the R142C mutation in the NOTCH3 gene (corresponding to human R141C).
• Histological analysis and Magnetic Resonance Imaging (MRI) to assess for CADASIL-like phenotypes.
• Analysis of NOTCH3 receptor processing and ectodomain accumulation.

Main Results:

• CADASIL(R142C) mice did not exhibit an apparent CADASIL-like phenotype.
• The NOTCH3 (R142C) receptor was processed normally in mice.
• No significant accumulation of the NOTCH3 ectodomain was observed in the mouse model, unlike in human patients.

Conclusions:

• The R142C NOTCH3 mutation, common in human CADASIL, does not induce a detectable phenotype in the generated mouse model.
• Discrepancies between mouse and human responses to the same germline mutation warrant further investigation into species-specific mechanisms.
• This mouse model may not fully recapitulate the pathogenesis of CADASIL, highlighting the complexity of vascular dementia.