| Texto completo | |
| Autor(es): Mostrar menos - |
Lackie, Rachel E.
;
Razzaq, Abdul R.
;
Farhan, Sali M. K.
;
Qiu, Lily R.
;
Moshitzky, Gilli
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Beraldo, Flavio H.
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Lopes, Marilene H.
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Maciejewski, Andrzej
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Gros, Robert
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Fan, Jue
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Choy, Wing-Yiu
;
Greenberg, David S.
;
Martins, Vilma R.
;
Duennwald, Martin L.
;
Lerch, Jason P.
;
Soreq, Hermona
;
Prado, Vania F.
;
Prado, Marco A. M.
Número total de Autores: 18
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| 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 |