Potent inhibitors of amyloid β fibrillization, 4,5-dianilinophthalimide and staurosporine aglycone, enhance degradation of preformed aggregates of mutant Notch3.
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.
Takahashi
Keikichi
K
Department of Vascular Dementia Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology (NCGG), Aichi, Japan.
Adachi
Kayo
K
Kunimoto
Shohko
S
Wakita
Hideaki
H
Takeda
Kazuya
K
Watanabe
Atsushi
A
D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D046589:CADASIL / Q000235:genetics / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology*; D009154:Mutation; D010797:Phthalimides / Q000494:pharmacology*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D002227:Carbazoles; D026121:Indole Alkaloids; C499374:NOTCH3 protein, human; D010797:Phthalimides; D000071656:Receptor, Notch3; D051880:Receptors, Notch; C049985:staurosporine aglycone; C098874:4,5-dianilinophthalimide