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

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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.

• Tipo de documento: Artigo Científico
• Fonte: Journal of Neurochemistry; v. 153, n. 6, p. 32-pg., 2019-10-31.

Resumo

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)

• Processo FAPESP: 16/00440-9 - Impacto da expressão da co-chaperona STIP1 na aquisição de pluripotência induzida por Oct4 em fibroblastos murinos
• Beneficiário: Marilene Hohmuth Lopes
• Modalidade de apoio: Bolsas no Exterior - Pesquisa
• Processo FAPESP: 17/20271-0 - Estudo da proteína prion na dinâmica de módulos multiproteicos de sinalização associados a stemness de células de glioblastoma: seu papel como marcador funcional e potencial alvo terapêutico
• Beneficiário: Marilene Hohmuth Lopes
• Modalidade de apoio: Auxílio à Pesquisa - Regular