Chaperone networks are dysregulated with aging, but whether compromised Hsp70/Hsp90 chaperone function can contribute to neuronal resilience 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. We combined in‐depth analysis of chaperone genes in human datasets, analysis of a neuronal cell line lacking STI1 and of a mouse line with a hypomorphic Stip1 allele to investigate the requirement of STI1‐mediated regulation for chaperone function and its role in aging. Our experiments revealed that dysfunctional STI1 activity compromised Hsp70/Hsp90 chaperone network and neuronal resilience. The levels of a set of Hsp90 co‐chaperones and client proteins were selectively affected by dysfunctional STI1, suggesting that their stability depends on functional Hsp70/Hsp90 machinery. Analysis of human databases revealed a subset of co‐chaperones, including STI1, whose loss of function are incompatible with life in mammals, albeit they are not essential in yeast. Importantly, mice expressing a hypomorphic STI1 allele presented spontaneous age‐dependent hippocampal neurodegeneration and reduced hippocampal volume, with consequent spatial memory deficit. We suggest that impaired STI1 function compromises Hsp70‐Hsp90 chaperone activity in mammals and can by itself cause age‐dependent hippocampal neurodegeneration in mice.
Modulation of hippocampal neuronal resilience during aging by the Hsp70/Hsp90 co‐chaperone STI1
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