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CADASIL-causing mutations do not alter Notch3 receptor processing and activation

Lookup NU author(s): Dr Roger Low, Professor Raj Kalaria


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CADASIL is associated with mutations in the Notch3 gene but the causal mechanisms of the disorder remain unclear. We studied effects of widely established mutations on Notch3 receptor processing and ligand-mediated activation in stable lines of HEK293 and SH-SY5Y cells expressing either human wild-type or mutant Notch3 receptor. None of the four mutations (R90C, R133C, C185R and R449C) affected quantities of the full-length, amino-terminal or carboxyl-terminal fragments and did not impair intracellular trafficking in both cell types. The Jagged 1, Jagged 2 and Delta ligand-mediated S2 site cleavage and signal transduction were also observed to be similar in both wild-type and mutants, which exhibited similar rates of degradation of full-length, amino-terminal and carboxyl-terminal fragments. Our results suggest that the arteriopathy in CADASIL is caused by other mechanisms not necessarily involving Notch3 processing and activation. © 2006 Lippincott Williams & Wilkins.

Publication metadata

Author(s): Low W-C, Santa Y, Takahashi K, Tabira T, Kalaria RN

Publication type: Article

Publication status: Published

Journal: NeuroReport

Year: 2006

Volume: 17

Issue: 10

Pages: 945-949

ISSN (print): 0959-4965

ISSN (electronic): 1473-558X

Publisher: Lippincott Williams & Wilkins


DOI: 10.1097/01.wnr.0000223394.66951.48

PubMed id: 16791082


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Funder referenceFunder name
G0400074Medical Research Council
G0502157Medical Research Council
G0500247Medical Research Council