Mutations in NOTCH3 cause the formation and retention of aggregates in the endoplasmic reticulum, leading to impaired cell proliferation

Keikichi Takahashi, Kayo Adachi, Kaichi Yoshizaki, Shohko Kunimoto, Raj N. Kalaria, Atsushi Watanabe

研究成果: Article

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Mutations in the human NOTCH3 gene cause cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), but the pathogenic mechanisms of the disorder remain unclear. We investigated the cytotoxic properties of mutant Notch3 using stable cell lines with inducible expression of either wild-type or two mutants p.R133C and p.C185R. We found that both mutants of Notch3 were prone to aggregation and retained in the endoplasmic reticulum (ER). The turnover rates of the mutated Notch3 proteins were strikingly slow, with half-lives greater than 6 days, whereas wild-type Notch3 was rapidly degraded, with a half-life of 0.7 days. The expression of mutant Notch3 also impaired cell proliferation compared with wild-type Notch3. In addition, cell lines expressing mutant Notch3 were more sensitive to proteasome inhibition resulting in cell death. These findings suggest that prolonged retention of mutant Notch3 aggregates in the ER decreases cell growth and increases sensitivity to other stresses. It is also possible that the aggregate-prone property of mutant Notch3 contributes to a pathogenic mechanism underlying CADASIL.

元の言語English
記事番号ddp468
ページ(範囲)79-89
ページ数11
ジャーナルHuman molecular genetics
19
発行部数1
DOI
出版物ステータスPublished - 2009 10 13

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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