The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition

• Published in: The FASEB journal Vol. 30; no. 4; p. 1656
• Main Authors: Moll, Lorna, Ben-Gedalya, Tziona, Reuveni, Hadas, Cohen, Ehud
• Format: Journal Article
• Language: English
• Published: United States 01.04.2016
• Subjects: Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - metabolism; Animals; Blotting, Western; Caenorhabditis elegans - drug effects; Caenorhabditis elegans - metabolism; Cell Line, Tumor; Cells, Cultured; CHO Cells; Cricetinae; Cricetulus; Gene Expression - drug effects; Homeostasis - drug effects; Homeostasis - physiology; Insulin-Like Growth Factor I - metabolism; Mice; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Neurodegenerative Diseases - metabolism; NIH 3T3 Cells; Organic Chemicals - pharmacology; PC12 Cells; Prions - antagonists & inhibitors; Prions - metabolism; Proteasome Endopeptidase Complex - metabolism; Proteins - metabolism; Pyrogallol - analogs & derivatives; Pyrogallol - pharmacology; Rats; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - drug effects; Signal Transduction - physiology; Thioamides - pharmacology; neurodegeneration; chaperones; aggresome; protein degradation
• ISSN: 1530-6860
• DOI: 10.1096/fj.15-281675

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.