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Modulation of hippocampal neuronal resilience during aging by the Hsp70/Hsp90 co‐chaperone STI1.
- Source :
- Journal of Neurochemistry; Jun2020, Vol. 153 Issue 6, p727-758, 32p
- Publication Year :
- 2020
-
Abstract
- 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- MICE
SPATIAL memory
HUMAN genes
CELL lines
CELL analysis
NEURODEGENERATION
Subjects
Details
- Language :
- English
- ISSN :
- 00223042
- Volume :
- 153
- Issue :
- 6
- Database :
- Complementary Index
- Journal :
- Journal of Neurochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 143745454
- Full Text :
- https://doi.org/10.1111/jnc.14882