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.

中文翻译：

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蛋白酶体作图揭示了组织对蛋白质聚集的敏感性中的性二态性。

蛋白酶体中的缺陷可导致病理性蛋白病。然而，性别和组织特异性敏感性对蛋白毒性应激的致病作用仍然难以捉摸。在这里，我们在雄性和雌性小鼠的9个组织中绘制了蛋白酶体活性图，并证明了蛋白酶体活性中的强性二态性，其中雌性在几个组织中具有明显更高的活性。此外，我们报告了蛋白酶体活性之间的巨大差异，而与蛋白酶体浓度无关，这在压力条件下会加剧。在SOD1 ALS小鼠模型中确认了蛋白酶体活性的性别二态性，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。