Division of Hematology/Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA.
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
EMBO Rep. 2020 Apr 3;21(4):e48978. doi: 10.15252/embr.201948978. Epub 2020 Feb 23.
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.
蛋白酶体的缺陷可导致病理性的蛋白构象病。然而，蛋白酶体应激的性别和组织特异性敏感性的致病作用仍然难以捉摸。在这里，我们绘制了九种组织中蛋白酶体的活性图谱，包括雄性和雌性小鼠，并证实了蛋白酶体活性存在强烈的性别二态性，其中雌性在几种组织中的活性明显更高。此外，我们报告了组织间蛋白酶体活性的巨大差异，这些差异独立于蛋白酶体浓度，在应激条件下会加剧。SOD1 ALS 小鼠模型中证实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。我们的研究结果为组织对蛋白质稳态应激的敏感性和神经退行性蛋白构象病进展中的性别差异提供了机制上的见解。
