A hypomorphic Stip1 allele reveals the requirement for chaperone networks in mouse development and aging

Lackie, R.; Lopes, M. H.; Farhan, S. M. K.; Razzaq, A.; Moshitzky, G.; Prado, M. B.; Beraldo, F. H.; Maciejewski, A.; Gros, R.; Fan, J.; Choy, W.-Y.; Greenberg, D.; Martins, V. R.; Duennwald, M.; Soreq, H.; Prado, V. F.; Prado, M. A. M.

doi:10.1101/258673

bioRxiv · 10.1101/258673

A hypomorphic Stip1 allele reveals the requirement for chaperone networks in mouse development and aging

Lackie, R.·Lopes, M. H.·Farhan, S. M. K.·Razzaq, A.·Moshitzky, G.·Prado, M. B.·Beraldo, F. H.·Maciejewski, A.·Gros, R.·Fan, J.·Choy, W.-Y.·Greenberg, D.·Martins, V. R.·Duennwald, M.·Soreq, H.·Prado, V. F.·Prado, M. A. M.

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Abstract

Chaperone networks are dysregulated with aging and neurodegenerative disease, but whether compromised Hsp70/Hsp90 chaperone function directly contributes to neuronal degeneration is unknown. Stress-inducible phosphoprotein-1 (STI1; STIP1; HOP) is a co-chaperone that simultaneously interacts with Hsp70 and Hsp90, but whose function in vivo remains poorly understood. To investigate the requirement of STI1-mediated regulation of the chaperone machinery in aging we combined analysis of a mouse line with a hypomorphic Stip1 allele, with a neuronal cell line lacking STI1 and in-depth analyses of chaperone genes in human datasets. Loss of STI1 function severely disturbed the Hsp70/Hsp90 machinery in vivo, and all client proteins tested and a subset of cochaperones presented decreased levels. Importantly, mice expressing a hypomorphic STI1 allele showed spontaneous age-dependent hippocampal neurodegeneration, with consequent spatial memory deficits. STI1 is a critical node for the chaperone network and it can contribute to age-dependent hippocampal neurodegeneration.

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Lackie, R., Lopes, M. H., Farhan, S. M. K., Razzaq, A., Moshitzky, G., Prado, M. B., Beraldo, F. H., Maciejewski, A., Gros, R., Fan, J., Choy, W.-Y., Greenberg, D., Martins, V. R., Duennwald, M., Soreq, H., Prado, V. F., Prado, M. A. M.. 2018-02-01. A hypomorphic Stip1 allele reveals the requirement for chaperone networks in mouse development and aging. https://doi.org/10.1101/258673

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