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

Aging Cell

Tayir El-Ami²  Lorna Moll²  Filipa Carvalhal Marques²  Yuli Volovik²  Hadas Reuveni¹ 

[1] NovoTyr Therapeutics Ltd., Tel Hai, Israel;Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel – Canada (IMRIC), The Hebrew University School of Medicine, Jerusalem, Israel

关键词: aging;    C. elegans;    insulin/IGF signaling inhibitor;    neurodegeneration;    proteostasis;   

DOI  :  10.1111/acel.12171

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.