Doxycycline promotes proteasome fitness in the central nervous system

Abstract Several studies reported that mitochondrial stress induces cytosolic proteostasis in yeast and C. elegans. Notably, inhibition of mitochondrial translation with doxcycyline decreases the toxicity of β-amyloid aggregates, in a C. elegans. However, how mitochondrial stress activates cytosolic...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Edmund Charles Jenkins, Matthew J. O’Connell, Giovanni Manfredi, Doris Germain
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e192bb23a88c41f3aa470441a552b7ef
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:e192bb23a88c41f3aa470441a552b7ef
record_format	dspace
spelling	oai:doaj.org-article:e192bb23a88c41f3aa470441a552b7ef2021-12-02T16:45:54ZDoxycycline promotes proteasome fitness in the central nervous system10.1038/s41598-021-96540-z2045-2322https://doaj.org/article/e192bb23a88c41f3aa470441a552b7ef2021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96540-zhttps://doaj.org/toc/2045-2322Abstract Several studies reported that mitochondrial stress induces cytosolic proteostasis in yeast and C. elegans. Notably, inhibition of mitochondrial translation with doxcycyline decreases the toxicity of β-amyloid aggregates, in a C. elegans. However, how mitochondrial stress activates cytosolic proteostasis remains unclear. Further whether doxycycline has this effect in mammals and in disease relevant tissues also remains unclear. We show here that doxycycline treatment in mice drastically reduces the accumulation of proteins destined for degradation by the proteasome in a CNS region-specific manner. This effect is associated with the activation of the ERα axis of the mitochondrial unfolded protein response (UPRmt), in both males and females. However, sexually dimorphic mechanisms of proteasome activation were observed. Doxycycline also activates the proteasome in fission yeast, where ERα is not expressed. Rather, the ancient ERα-coactivator Mms19 regulates this response in yeast. Our results suggest that the UPRmt initiates a conserved mitochondria-to-cytosol stress signal, resulting in proteasome activation, and that this signal has adapted during evolution, in a sex and tissue specific-manner. Therefore, while our results support the use of doxycycline in the prevention of proteopathic diseases, they also indicate that sex is an important variable to consider in the design of future clinical trials using doxycycline.Edmund Charles JenkinsMatthew J. O’ConnellGiovanni ManfrediDoris GermainNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Edmund Charles Jenkins Matthew J. O’Connell Giovanni Manfredi Doris Germain Doxycycline promotes proteasome fitness in the central nervous system
description	Abstract Several studies reported that mitochondrial stress induces cytosolic proteostasis in yeast and C. elegans. Notably, inhibition of mitochondrial translation with doxcycyline decreases the toxicity of β-amyloid aggregates, in a C. elegans. However, how mitochondrial stress activates cytosolic proteostasis remains unclear. Further whether doxycycline has this effect in mammals and in disease relevant tissues also remains unclear. We show here that doxycycline treatment in mice drastically reduces the accumulation of proteins destined for degradation by the proteasome in a CNS region-specific manner. This effect is associated with the activation of the ERα axis of the mitochondrial unfolded protein response (UPRmt), in both males and females. However, sexually dimorphic mechanisms of proteasome activation were observed. Doxycycline also activates the proteasome in fission yeast, where ERα is not expressed. Rather, the ancient ERα-coactivator Mms19 regulates this response in yeast. Our results suggest that the UPRmt initiates a conserved mitochondria-to-cytosol stress signal, resulting in proteasome activation, and that this signal has adapted during evolution, in a sex and tissue specific-manner. Therefore, while our results support the use of doxycycline in the prevention of proteopathic diseases, they also indicate that sex is an important variable to consider in the design of future clinical trials using doxycycline.
format	article
author	Edmund Charles Jenkins Matthew J. O’Connell Giovanni Manfredi Doris Germain
author_facet	Edmund Charles Jenkins Matthew J. O’Connell Giovanni Manfredi Doris Germain
author_sort	Edmund Charles Jenkins
title	Doxycycline promotes proteasome fitness in the central nervous system
title_short	Doxycycline promotes proteasome fitness in the central nervous system
title_full	Doxycycline promotes proteasome fitness in the central nervous system
title_fullStr	Doxycycline promotes proteasome fitness in the central nervous system
title_full_unstemmed	Doxycycline promotes proteasome fitness in the central nervous system
title_sort	doxycycline promotes proteasome fitness in the central nervous system
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e192bb23a88c41f3aa470441a552b7ef
work_keys_str_mv	AT edmundcharlesjenkins doxycyclinepromotesproteasomefitnessinthecentralnervoussystem AT matthewjoconnell doxycyclinepromotesproteasomefitnessinthecentralnervoussystem AT giovannimanfredi doxycyclinepromotesproteasomefitnessinthecentralnervoussystem AT dorisgermain doxycyclinepromotesproteasomefitnessinthecentralnervoussystem
_version_	1718383485822959616

Doxycycline promotes proteasome fitness in the central nervous system

Ejemplares similares