Modulation of hippocampal neuronal resilience during aging by the Hsp70/Hsp90 co‐chaperone STI1

• Published in: Journal of neurochemistry 2020-06, Vol.153 (6), p.727-758
• Main Authors: Lackie, Rachel E., Razzaq, Abdul R., Farhan, Sali M. K., Qiu, Lily R., Moshitzky, Gilli, Beraldo, Flavio H., Lopes, Marilene H., Maciejewski, Andrzej, Gros, Robert, Fan, Jue, Choy, Wing‐Yiu, Greenberg, David S., Martins, Vilma R., Duennwald, Martin L., Lerch, Jason P., Soreq, Hermona, Prado, Vania F., Prado, Marco A. M.
• Format: Article
• Language: English
• Subjects: Aging; Alleles; Chaperones; Hippocampus; HOP/STI1; Hsp70 protein; Hsp70/Hsp90; Hsp90 protein; Mammals; Memory tasks; Neurodegeneration; Neuromodulation; Resilience; Spatial analysis; Spatial memory; Stability analysis; Yeasts
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14882

Chaperone networks are dysregulated with aging, but whether compromised Hsp70/Hsp90 chaperone function disturbs 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 for STI1 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 reduced levels of 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 is 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. Cover Image for this issue: doi: 10.1111/jnc.14749. Complete knock‐out of the Hsp70/Hsp90 co‐chaperone STI1 is embryonically lethal, therefore, to understand how STI1 affects neurons we generated mice carrying a hypomorphic allele for STI1. Mice with 80% less STI1 are viable and were used to characterize the impact of STI1 in the Hsp90 chaperone machinery in the aging brain. We found reduced expression of a subset of Hsp90 clients and Hsp90 accessory proteins. These mice present selective age‐dependent neurodegeneration in the hippocampus with correspondent spatial memory deficits. Our work highlights the requirement for STI1 in hippocampal neuronal resilience and function during aging. Cover Image for this issue: doi: 10.1111/jnc.14749.