A novel inhibitor of the insulin/IGF signaling pathway protects from age‐onset, neurodegeneration‐linked proteotoxicity

• Published in: Aging cell Vol. 13; no. 1; pp. 165 - 174
• Main Authors: El‐Ami, Tayir, Moll, Lorna, Carvalhal Marques, Filipa, Volovik, Yuli, Reuveni, Hadas, Cohen, Ehud
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.02.2014; BlackWell Publishing Ltd
• Subjects: Aging; Aging - metabolism; Aging - pathology; Alzheimer's disease; Amyloid beta-Peptides - toxicity; Animals; C. elegans; Caenorhabditis elegans - drug effects; Caenorhabditis elegans - genetics; Caenorhabditis elegans - radiation effects; Cell Line, Tumor; Gene Expression Regulation - drug effects; Hot Temperature; Humans; Insulin; Insulin - metabolism; Insulin-Like Growth Factor I - metabolism; insulin/IGF signaling inhibitor; Longevity - drug effects; Longevity - radiation effects; Mice; Models, Animal; Nematoda; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Nervous system diseases; Neurodegeneration; Neuroprotective Agents - pharmacology; Original; Peptides - toxicity; Proteins; proteostasis; Proto-Oncogene Proteins c-akt - metabolism; Receptor, IGF Type 1 - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - radiation effects; Stress, Physiological - drug effects; Stress, Physiological - genetics; Stress, Physiological - radiation effects; Ultraviolet Rays; C. elegans; neurodegeneration; insulin/IGF signaling inhibitor; aging; proteostasis
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.12171

Summary 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.