title: A novel inhibitor of the insulin/IGF signaling pathway protects from age-onset, neurodegeneration-linked proteotoxicity.
abstract: Aging manipulation is an emerging strategy aimed to postpone the manifestation of late-onset neurodegenerative disorders such as Alzheimer's (AD) and Huntington's diseases (HD) and to slow their progression once emerged. Reducing the activity of the insulin/IGF signaling cascade (IIS), a prominent aging-regulating pathway, protects worms from proteotoxicity of various aggregative proteins, including the AD-associated peptide, Aβ- and the HD-linked peptide, polyQ40. Similarly, IGF1 signaling reduction protects mice from AD-like disease. These discoveries suggest that IIS inhibitors can serve as new drugs for the treatment of neurodegenerative maladies including AD and HD. Here, we report that NT219, a novel IIS inhibitor, mediates a long-lasting, highly efficient inhibition of this signaling cascade by a dual mechanism; it reduces the autophosphorylation of the IGF1 receptor and directs the insulin receptor substrates 1 and 2 (IRS 1/2) for degradation. NT219 treatment promotes stress resistance and protects nematodes from AD- and HD-associated proteotoxicity without affecting lifespan. Our discoveries strengthen the theme that IIS inhibition has a therapeutic potential as a cure for neurodegenerative maladies and point at NT219 as a promising compound for the treatment of these disorders through a selective manipulation of aging.
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel - Canada (IMRIC), The Hebrew University School of Medicine, Jerusalem, Israel.
authors.forename: Tayir
authors.initials: T
authors.lastname: El-Ami
authors.forename: Lorna
authors.initials: L
authors.lastname: Moll
authors.forename: Filipa
authors.initials: F
authors.lastname: Carvalhal Marques
authors.forename: Yuli
authors.initials: Y
authors.lastname: Volovik
authors.forename: Hadas
authors.initials: H
authors.lastname: Reuveni
authors.forename: Ehud
authors.initials: E
authors.lastname: Cohen
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects; D006358:Hot Temperature; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008136:Longevity / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D023421:Models, Animal; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010455:Peptides / Q000633:toxicity*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D014466:Ultraviolet Rays
chemical_list: D016229:Amyloid beta-Peptides; D007328:Insulin; D018696:Neuroprotective Agents; D010455:Peptides; C097188:polyglutamine; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt
keywords: C. elegans; aging; insulin/IGF signaling inhibitor; neurodegeneration; proteostasis