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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Lackie, Rachel E. [1, 2] ; Razzaq, Abdul R. [1, 2] ; Farhan, Sali M. K. [3, 4] ; Qiu, Lily R. [5, 6] ; Moshitzky, Gilli [7] ; Beraldo, Flavio H. [8, 1] ; Lopes, Marilene H. [1, 9] ; Maciejewski, Andrzej [10] ; Gros, Robert [8, 11, 1] ; Fan, Jue [1] ; Choy, Wing-Yiu [10] ; Greenberg, David S. [7] ; Martins, Vilma R. [12] ; Duennwald, Martin L. [13, 14] ; Lerch, Jason P. [15, 5, 6] ; Soreq, Hermona [7] ; Prado, Vania F. [8, 1, 2, 13] ; Prado, Marco A. M. [8, 1, 2, 13]
Total Authors: 18
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[1] Univ Western Ontario, Robarts Res Inst, 1151 Richmond St N, London, ON N6A 5B7 - Canada
[2] Univ Western Ontario, Program Neurosci, London, ON - Canada
[3] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Genom Med, Analyt & Translat Genet Unit, Boston, MA 02115 - USA
[4] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Boston, MA - USA
[5] Hosp Sick Children, Mouse Imaging Ctr, Toronto, ON - Canada
[6] Hosp Sick Children, Dept Neurosci & Mental Hlth, Toronto, ON - Canada
[7] Hebrew Univ Jerusalem, Edmond & Lily Safra Ctr Brain Sci, Alexander Silberman Inst Life Sci, Dept Biol Chem, Jerusalem - Israel
[8] Univ Western Ontario, Dept Physiol & Pharmacol, London, ON - Canada
[9] Univ Sao Paulo, Inst Biomed Sci, Dept Cell & Dev Biol, Lab Neurobiol & Stem Cells, Sao Paulo - Brazil
[10] Univ Western Ontario, Dept Biochem, London, ON - Canada
[11] Univ Western Ontario, Dept Med, London, ON - Canada
[12] Int Res Ctr, AC Camargo Canc Ctr, Sao Paulo - Brazil
[13] Univ Western Ontario, Schulich Sch Med & Dent, Dept Anat & Cell Biol, London, ON - Canada
[14] Univ Western Ontario, Dept Pathol & Lab Med, London, ON - Canada
[15] Univ Toronto, Dept Med Biophys, Toronto, ON - Canada
Total Affiliations: 15
Document type: Journal article
Source: Journal of Neurochemistry; OCT 2019.
Web of Science Citations: 0

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. (AU)

FAPESP's process: 17/20271-0 - Role of prion protein in the dynamic of multiprotein signaling modules related to stemness of glioblastoma stem cells: its functional role and potential therapeutic target
Grantee:Marilene Hohmuth Lopes
Support type: Regular Research Grants
FAPESP's process: 16/00440-9 - Impact of co-chaperone STIP1 expression in the pluripotency acquision induced by Oct4 in murine fibroblasts
Grantee:Marilene Hohmuth Lopes
Support type: Scholarships abroad - Research