Doxycycline promotes proteasome fitness in the central nervous system.
Doxycycline promotes proteasome fitness in the central nervous system.
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强力霉素促进中枢神经系统蛋白酶体适应性。
DOI：
10.1038/s41598-021-96540-z
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发表时间：
2021-08-20
影响因子：
4.6
通讯作者：
Germain D
中科院分区：
文献类型：
--
作者：
Jenkins EC;O'Connell MJ;Manfredi G;Germain D
一些研究报道线粒体应激诱导酵母和C.优雅值得注意的是，在C.优雅然而，线粒体应激如何激活胞质蛋白质稳态仍不清楚。此外，多西环素在哺乳动物和疾病相关组织中是否具有这种作用也尚不清楚。我们在这里表明，多西环素治疗小鼠大大减少了蛋白质的积累，注定由蛋白酶体在中枢神经系统区域特异性的方式降解。在雄性和雌性动物中，该效应与线粒体未折叠蛋白反应（UPRmt）的ERα轴激活相关。然而，观察到蛋白酶体激活的性二态机制。多西环素还激活裂殖酵母中的蛋白酶体，其中ERα不表达。相反，古老的ERα-辅激活因子Mms 19在酵母中调节这种反应。我们的研究结果表明，UPRmt启动一个保守的细胞质到胞质溶胶的压力信号，导致蛋白酶体激活，这个信号已经适应了进化过程中，在性别和组织特异性的方式。因此，虽然我们的研究结果支持使用多西环素预防蛋白质病，他们也表明，性别是一个重要的变量，考虑在未来的临床试验设计使用多西环素。
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.
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影响因子：
8.8
作者：
Moullan N;Mouchiroud L;Wang X;Ryu D;Williams EG;Mottis A;Jovaisaite V;Frochaux MV;Quiros PM;Deplancke B;Houtkooper RH;Auwerx J
通讯作者：
Auwerx J
影响因子：
7.7
作者：
Jenkins, Edmund Charles;Shah, Nagma;Germain, Doris
通讯作者：
Germain, Doris
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8
作者：
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通讯作者：
Martin, F.
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作者：
Papa, Luena;Germain, Doris
通讯作者：
Germain, Doris
影响因子：
3
作者：
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通讯作者：
Germain, Doris