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.
Bibliographical noteFunding Information:
This study was generously supported by the Rosetrees Trust (to E.C.) and the European Research Council (ERC#281010; to E.C.). E.C. and H.R. are listed as inventors in a pending patent application entitled "IGF-1R (licensed to TyrNovo) signaling pathway inhibitors useful in the treatment of neurodegenerative diseases." E.C. and L.M. designed and initiated this study; E.C., H.R., and L.M. wrote the manuscript; H.R. conducted the development of NT219; L.M. performed all of the experimental work; and T.B.-G. performed Western blot and immunofluorescence experiments.
© 2016 FASEB.
- Protein degradation