Cambridge Institute for Medical Research, The Keith Peters Building, Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, United Kingdom.
UK Dementia Research Institute, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, United Kingdom.
Hum Mol Genet. 2024 Aug 18;33(17):1506-1523. doi: 10.1093/hmg/ddae085.
The ubiquitin-proteasome system mediates the degradation of a wide variety of proteins. Proteasome dysfunction is associated with neurodegenerative diseases and neurodevelopmental disorders in humans. Here we identified mutations in PSMC5, an AAA ATPase subunit of the proteasome 19S regulatory particle, in individuals with neurodevelopmental disorders, which were initially considered as variants of unknown significance. We have now found heterozygotes with the following mutations: P320R (6 individuals), R325W, Q160A, and one nonsense mutation at Q69. We focused on understanding the functional consequence of PSMC5 insufficiency and the P320R mutation in cells and found that both impair proteasome function and activate apoptosis. Interestingly, the P320R mutation impairs proteasome function by weakening the association between the 19S regulatory particle and the 20S core particle. Our study supports that proteasome dysfunction is the pathogenic cause of neurodevelopmental disorders in individuals carrying PSMC5 variants.
泛素-蛋白酶体系统介导各种蛋白质的降解。蛋白酶体功能障碍与人类的神经退行性疾病和神经发育障碍有关。在这里，我们在患有神经发育障碍的个体中鉴定出了蛋白酶体 19S 调节颗粒的 AAA ATP 酶亚基 PSMC5 的突变，这些突变最初被认为是意义不明的变异。我们现在已经发现了以下突变的杂合子：P320R（6 个人）、R325W、Q160A 和一个 Q69 的无义突变。我们专注于理解 PSMC5 不足和 P320R 突变在细胞中的功能后果，发现这两种突变都损害了蛋白酶体功能并激活了细胞凋亡。有趣的是，P320R 突变通过削弱 19S 调节颗粒与 20S 核心颗粒之间的关联来损害蛋白酶体功能。我们的研究支持携带 PSMC5 变异的个体中蛋白酶体功能障碍是神经发育障碍的致病原因。
