Proteasome mapping reveals sexual dimorphism in tissue-specific sensitivity to protein aggregations
Proteasome mapping reveals sexual dimorphism in tissue-specific sensitivity to protein aggregations
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DOI：
10.15252/embr.201948978
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发表时间：
2020-02-23
期刊：
影响因子：
7.7
通讯作者：
Germain, Doris
中科院分区：
文献类型：
--
作者：
Jenkins, Edmund Charles;Shah, Nagma;Germain, Doris
蛋白酶体的缺陷可导致病理性蛋白质病。然而，性别和组织特异性的敏感性蛋白毒性应激的致病作用仍然难以捉摸。在这里，我们映射的蛋白酶体活性在9个组织，在男性和女性小鼠，并表现出强烈的性二态性蛋白酶体活性，女性在几个组织中具有显着较高的活性。此外，我们报告了组织之间蛋白酶体活性的巨大差异，独立于蛋白酶体浓度，这在应激条件下加剧。在SOD1 ALS小鼠模型中证实了蛋白酶体活性的性二态性，其中脊髓，一种蛋白酶体活性相对较低的组织，受到严重影响。我们的研究结果提供了对组织特异性敏感性的机制洞察，以蛋白稳态应激和神经退行性蛋白病进展的性别差异。
Defects in the proteasome can result in pathological proteinopathies. However, the pathogenic role of sex- and tissue-specific sensitivity to proteotoxic stress remains elusive. Here, we map the proteasome activity across nine tissues, in male and female mice, and demonstrate strong sexual dimorphism in proteasome activity, where females have significantly higher activity in several tissues. Further, we report drastic differences in proteasome activity among tissues, independently of proteasome concentration, which are exacerbated under stress conditions. Sexual dimorphism in proteasome activity is confirmed in a SOD1 ALS mouse model, in which the spinal cord, a tissue with comparatively low proteasome activity, is severely affected. Our results offer mechanistic insight into tissue-specific sensitivities to proteostasis stress and into sex differences in the progression of neurodegenerative proteinopathies.