J Neurochem. 2019 Sep 28. doi: 10.1111/jnc.14882. [Epub ahead of print]
Modulation of hippocampal neuronal resilience during aging by the Hsp70/Hsp90 co-chaperone STI1.
Robarts Research Institute, Program in Neuroscience, Department of Physiology and Pharmacology, Department of Biochemistry, Department of Medicine, Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Ontario, Canada. Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, and The Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, Massachusetts, USA. Mouse Imaging Centre, Department of Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario, Canada. Department of Biological Chemistry, The Edmond and Lily Safra Center for Brain Sciences, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel. Laboratory of Neurobiology and Stem cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil. International Research Center, A.C. Camargo Cancer Center, São Paulo, Brazil. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Service type: Knockout mice
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. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.View Publication