Department of Biochemistry, West Virginia University School of Medicine, Morgantown, West Virginia, USA.
Department of Biochemistry, West Virginia University School of Medicine, Morgantown, West Virginia, USA.
J Biol Chem. 2022 Oct;298(10):102415. doi: 10.1016/j.jbc.2022.102415. Epub 2022 Aug 23.
Virtually all age-related neurodegenerative diseases (NDs) can be characterized by the accumulation of proteins inside and outside the cell that are thought to significantly contribute to disease pathogenesis. One of the cell's primary systems for the degradation of misfolded/damaged proteins is the ubiquitin proteasome system (UPS), and its impairment is implicated in essentially all NDs. Thus, upregulating this system to combat NDs has garnered a great deal of interest in recent years. Various animal models have focused on stimulating 26S activity and increasing 20S proteasome levels, but thus far, none have targeted intrinsic activation of the 20S proteasome itself. Therefore, we constructed an animal model that endogenously expresses a hyperactive, open gate proteasome in Caenorhabditis elegans. The gate-destabilizing mutation that we introduced into the nematode germline yielded a viable nematode population with enhanced proteasomal activity, including peptide, unstructured protein, and ubiquitin-dependent degradation activities. We determined these nematodes showed a significantly increased lifespan and substantial resistance to oxidative and proteotoxic stress but a significant decrease in fecundity. Our results show that introducing a constitutively active proteasome into a multicellular organism is feasible and suggests targeting the proteasome gating mechanism as a valid approach for future age-related disease research efforts in mammals.
几乎所有与年龄相关的神经退行性疾病（NDs）都可以表现为细胞内外蛋白质的积累，这些蛋白质被认为对疾病的发病机制有重要贡献。细胞内用于降解错误折叠/受损蛋白质的主要系统之一是泛素蛋白酶体系统（UPS），其功能障碍与几乎所有 NDs 都有关。因此，近年来，上调该系统以对抗 NDs 引起了极大的关注。各种动物模型都集中在刺激 26S 活性和增加 20S 蛋白酶体水平上，但到目前为止，还没有针对 20S 蛋白酶体本身的内在激活。因此，我们构建了一种在秀丽隐杆线虫中内源表达高活性、开闸门蛋白酶体的动物模型。我们引入线虫生殖系的门控破坏突变产生了一个可行的线虫种群，具有增强的蛋白酶体活性，包括肽、无结构蛋白和泛素依赖性降解活性。我们确定这些线虫的寿命显著延长，对氧化和蛋白毒性应激的抵抗力显著增强，但繁殖力显著降低。我们的结果表明，在多细胞生物中引入组成型活性蛋白酶体是可行的，并表明靶向蛋白酶体门控机制是未来哺乳动物与年龄相关疾病研究的有效方法。
