Potent inhibitors of amyloid β fibrillization, 4,5-dianilinophthalimide and staurosporine aglycone, enhance degradation of preformed aggregates of mutant Notch3

Keikichi Takahashi, Kayo Adachi, Shohko Kunimoto, Hideaki Wakita, Kazuya Takeda, Atsushi Watanabe

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in human NOTCH3. We have recently reported that mutant Notch3 shows a greater propensity to form aggregates, and these aggregates resist degradation, leading to accumulation in the endoplasmic reticulum (ER). In this study, we searched for low-molecular compounds that decrease the amount of mutant Notch3 aggregates. Using a cell-based system, we found that degradation of preformed mutant aggregates was enhanced by treatment with either 4,5-dianilinophthalimide (DAPH) or staurosporine aglycone (SA), both of which inhibit amyloid β (Aβ) fibrillization. Regarding other low-molecular compounds interacting with Aβ fibrils, thioflavin T (ThT) also enhanced the clearance of mutant Notch3. These findings suggest that DAPH, SA, and ThT are potent reagents to dissociate the preformed aggregates of mutant Notch3 by disruption of intermolecular contacts of misfolded proteins. Our study may provide the basis for the development of a pharmacological therapy for CADASIL.

Original languageEnglish
Pages (from-to)54-58
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume402
Issue number1
DOIs
Publication statusPublished - 05-11-2010

Fingerprint

CADASIL
Amyloid
Degradation
Endoplasmic Reticulum
Pharmacology
Mutation
Proteins
staurosporine aglycone
thioflavin T
4,5-dianilinophthalimide
Therapeutics

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "Potent inhibitors of amyloid β fibrillization, 4,5-dianilinophthalimide and staurosporine aglycone, enhance degradation of preformed aggregates of mutant Notch3",
abstract = "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in human NOTCH3. We have recently reported that mutant Notch3 shows a greater propensity to form aggregates, and these aggregates resist degradation, leading to accumulation in the endoplasmic reticulum (ER). In this study, we searched for low-molecular compounds that decrease the amount of mutant Notch3 aggregates. Using a cell-based system, we found that degradation of preformed mutant aggregates was enhanced by treatment with either 4,5-dianilinophthalimide (DAPH) or staurosporine aglycone (SA), both of which inhibit amyloid β (Aβ) fibrillization. Regarding other low-molecular compounds interacting with Aβ fibrils, thioflavin T (ThT) also enhanced the clearance of mutant Notch3. These findings suggest that DAPH, SA, and ThT are potent reagents to dissociate the preformed aggregates of mutant Notch3 by disruption of intermolecular contacts of misfolded proteins. Our study may provide the basis for the development of a pharmacological therapy for CADASIL.",
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Potent inhibitors of amyloid β fibrillization, 4,5-dianilinophthalimide and staurosporine aglycone, enhance degradation of preformed aggregates of mutant Notch3. / Takahashi, Keikichi; Adachi, Kayo; Kunimoto, Shohko; Wakita, Hideaki; Takeda, Kazuya; Watanabe, Atsushi.

In: Biochemical and Biophysical Research Communications, Vol. 402, No. 1, 05.11.2010, p. 54-58.

Research output: Contribution to journalArticle

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AU - Wakita, Hideaki

AU - Takeda, Kazuya

AU - Watanabe, Atsushi

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N2 - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in human NOTCH3. We have recently reported that mutant Notch3 shows a greater propensity to form aggregates, and these aggregates resist degradation, leading to accumulation in the endoplasmic reticulum (ER). In this study, we searched for low-molecular compounds that decrease the amount of mutant Notch3 aggregates. Using a cell-based system, we found that degradation of preformed mutant aggregates was enhanced by treatment with either 4,5-dianilinophthalimide (DAPH) or staurosporine aglycone (SA), both of which inhibit amyloid β (Aβ) fibrillization. Regarding other low-molecular compounds interacting with Aβ fibrils, thioflavin T (ThT) also enhanced the clearance of mutant Notch3. These findings suggest that DAPH, SA, and ThT are potent reagents to dissociate the preformed aggregates of mutant Notch3 by disruption of intermolecular contacts of misfolded proteins. Our study may provide the basis for the development of a pharmacological therapy for CADASIL.

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