Doxycycline promotes proteasome fitness in the central nervous system.

TitleDoxycycline promotes proteasome fitness in the central nervous system.
Publication TypeJournal Article
Year of Publication2021
AuthorsJenkins ECharles, O'Connell MJ, Manfredi G, Germain D
JournalSci Rep
Date Published2021 Aug 20

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.

Alternate JournalSci Rep
PubMed ID34417525
PubMed Central IDPMC8379233
Grant ListR01GM124079 / NH / NIH HHS / United States
R01 NS084486 / NS / NINDS NIH HHS / United States
R01NS084486 / NH / NIH HHS / United States
R01 GM124079 / GM / NIGMS NIH HHS / United States
R01 NS062055 / NS / NINDS NIH HHS / United States