HSF-1 LONGEVITY/PROT · Identifying the Heat Shock Factor -1 Longevity Assurance and Proteostasis Co-regulators and Target genes

Identifying the Heat Shock Factor -1 Longevity Assurance and Proteostasis Co-regulators and Target genes

In the nematode Caenorhabditis elegans (C. elegans) the heat shock factor 1 (HSF-1) plays critical roles in a variety of cellular and organismal processes including development, stress response, the determination of lifespan and protection from toxic protein aggregation (proteotoxicity). Upon activation HSF-1 trimerizes, enters the nucleus and regulates the expression of its target gene networks. The longevity and counter proteotoxic functions of HSF-1 are closely associated with the highly conserved Insulin/IGF-1 signaling pathway (IIS). DAF-2, the sole C. elegans insulin/IGF-1 receptor, negatively regulates a few transcription factors including HSF-1 and the forkhead transcription factor, DAF-16. Thus, IIS reduction hyper-activates DAF-16 and HSF-1 which in turn mediate longevity, stress resistance and most importantly, provide protection from neurodegeneration-linked proteotoxicity. This protection points at IIS reduction as a novel therapeutic strategy that could postpone the onset of neurodegenerative maladies and alleviate their symptoms once emerged. However, to assess the potential of this approach it is critical to elucidate the temporal and mechanistic features of the IIS and its downstream transcription factors. This project was aimed to study the temporal and functional characteristics of HSF-1 as a lifespan determinant and counter-proteotoxic transcription factor. Using nematodes we found that HSF-1 is foremost important for longevity assurance and for the maintenance of protein homeostasis (proteostasis) during development. These findings were published in 2012 at Aging Cell (Volovik et al,. Aging Cell 2012 Jun;11(3):491-9). Since DAF-16 executes its longevity and proteostasis maintenance functions during adulthood we postulated that HSF-1 enables DAF-16 to promote stress resistance and protection from proteotoxicity by inducing during development the expression of genes that encode for proteins which serve as DAF-16 co-factors during adulthood. To test this hypothesis we first identified the genes that are regulated by HSF-1 during the lifespan-regulating period. Among these genes we characterized two that are DAF-16 co-factors. One, which we termed gtr-1, acts in neurons to regulate heat stress resistance in distal tissues. Surprisingly, the knockdown of gtr-1 has no effect on lifespan but provides partial protection from the aggregation of the Alzheimer's-associated peptide A-beta. This work, which sheds new light on the complex communication between tissues within an organism and supports the emerging theme that stress resistance comes at the expense of protein homeostasis, was published at the Journal of Neuroscience (Maman et al,. J Neurosci. 2013 Apr 3;33(14):6102-11). The second gene, nhl-1, exhibits similar features. Its expression is regulated by the IIS, it is expressed in chemosensory neurons and its knockdown reduces stress resistance and provides protection from toxic protein aggregation. A manuscript describing the roles of nhl-1 is in preparation and expected to be published in the near future. Our findings have critical importance for the evaluation of IIS reduction as a novel therapeutic approach aimed to treated late-onset disorders such as Alzheimer's disease by selective manipulation of the aging process. It highlighted the roles of inter-tissue communication in the regulation of protein homeostasis and identified specific genes which play roles in this mechanism. Further research will be required to develop this therapeutic strategy for the benefit of patients who suffer from neurodegenerative maladies and their families.

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