Objective Aberrant protein aggregation (proteotoxicity) is an underlying mechanistic event common to numerous late-onset human neurodegenerative maladies including Alzheimer’s (AD) disease. Recent studies indicated that the ageing process plays key roles in enabling protein aggregation to become toxic late in life. The insulin/IGF signaling pathway (IIS) is a major ageing, stress resistance and lifespan regulator in worms and mice. We found that IIS reduction protects worms and mice from toxicity associated with the AD linked peptide, Aβ. These findings point to the alteration of ageing by IIS reduction as a promising research avenue towards the development of neurodegeneration therapies. In the nematode C. elegans, both effects of IIS reduction; longevity and protection from proteotoxicity are dependent on the activity of the FOXO transcription factor DAF-16. However, these functions of DAF-16/FOXO differ temporally; in worms the mediation of longevity by DAF-16 is restricted to reproductive adulthood while protection from proteotoxicity extends also to late adulthood. This differential temporal activity pattern suggests that different DAF-16 co-factors and target genes play roles in the mediation of longevity and in protection from proteotoxicity. Thus, a careful characterization of the late life DAF-16 regulated protective mechanism is required to evaluate the therapeutic potential of IIS reduction as a future treatment for neurodegenerative disorders. Here I propose to use nematodes and mice to explore the DAF-16/FOXO co-factors and target genes that mediate stress resistance and protection from proteotoxicity in the aged organism. Dual experimental approach will be utilized to achieve this goal; a directed genetic screen for the identification of co-factors and temporally differential set of DNA microarrays for the recognition of late life DAF-16/FOX target genes. This project is expected to yield new insight and to serve as a platform for future studies. Fields of science natural sciencesbiological sciencesneurobiologymedical and health sciencesbasic medicineneurologydementiaalzheimernatural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological scienceszoologymammalogy Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-SG-LS5 - ERC Starting Grant - Neurosciences and neural disorders Call for proposal ERC-2011-StG_20101109 See other projects for this call Funding Scheme ERC-SG - ERC Starting Grant Coordinator THE HEBREW UNIVERSITY OF JERUSALEM Address Edmond j safra campus givat ram 91904 Jerusalem Israel See on map Activity type Higher or Secondary Education Establishments Principal investigator Ehud Cohen (Dr.) Administrative Contact Hani Ben-Yehuda (Ms.) Links Contact the organisation Opens in new window Website Opens in new window EU contribution No data Beneficiaries (1) Sort alphabetically Sort by EU Contribution Expand all Collapse all THE HEBREW UNIVERSITY OF JERUSALEM Israel EU contribution € 1 438 899,20 Address Edmond j safra campus givat ram 91904 Jerusalem See on map Activity type Higher or Secondary Education Establishments Principal investigator Ehud Cohen (Dr.) Administrative Contact Hani Ben-Yehuda (Ms.) Links Contact the organisation Opens in new window Website Opens in new window Other funding No data
