title: The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition.
abstract: The discovery that the alteration of aging by reducing the activity of the insulin/IGF-1 signaling (IIS) cascade protects nematodes and mice from neurodegeneration-linked, toxic protein aggregation (proteotoxicity) raises the prospect that IIS inhibitors bear therapeutic potential to counter neurodegenerative diseases. Recently, we reported that NT219, a highly efficient IGF-1 signaling inhibitor, protects model worms from the aggregation of amyloid β peptide and polyglutamine peptides that are linked to the manifestation of Alzheimer's and Huntington's diseases, respectively. Here, we employed cultured cell systems to investigate whether NT219 promotes protein homeostasis (proteostasis) in mammalian cells and to explore its underlying mechanisms. We found that NT219 enhances the aggregation of misfolded prion protein and promotes its deposition in quality control compartments known as "aggresomes." NT219 also elevates the levels of certain molecular chaperones but, surprisingly, reduces proteasome activity and impairs autophagy. Our findings show that IGF-1 signaling inhibitors in general and NT219 in particular can promote proteostasis in mammalian cells by hyperaggregating hazardous proteins, thereby bearing the potential to postpone the onset and slow the progression of neurodegenerative illnesses in the elderly.-Moll, L., Ben-Gedalya, T., Reuveni, H., Cohen, E. The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition.
authors.affiliation: *Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University School of Medicine, Jerusalem, Israel; and TyrNovo Limited, Herzliya Pituach, Israel.
authors.forename: Lorna
authors.initials: L
authors.lastname: Moll
authors.affiliation: *Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University School of Medicine, Jerusalem, Israel; and TyrNovo Limited, Herzliya Pituach, Israel.
authors.forename: Tziona
authors.initials: T
authors.lastname: Ben-Gedalya
authors.affiliation: *Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University School of Medicine, Jerusalem, Israel; and TyrNovo Limited, Herzliya Pituach, Israel.
authors.forename: Hadas
authors.initials: H
authors.lastname: Reuveni
authors.affiliation: *Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University School of Medicine, Jerusalem, Israel; and TyrNovo Limited, Herzliya Pituach, Israel ehudc@ekmd.huji.ac.il.
authors.forename: Ehud
authors.initials: E
authors.lastname: Cohen
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D015870:Gene Expression / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009930:Organic Chemicals / Q000494:pharmacology; D016716:PC12 Cells; D011328:Prions / Q000037:antagonists & inhibitors / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D011748:Pyrogallol / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013854:Thioamides / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D018832:Molecular Chaperones; C000609920:NT219 compound; D009930:Organic Chemicals; D011328:Prions; D011506:Proteins; D013854:Thioamides; D011748:Pyrogallol; D007334:Insulin-Like Growth Factor I; D046988:Proteasome Endopeptidase Complex
keywords: aggresome; chaperones; neurodegeneration; protein degradation