Department of Urology, The First Affiliated Hospital of Anhui Medical University, Institute of Urology, Anhui Medical University and Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, 230022, PR China.
Nanobio Laboratory, Institute of Life Sciences, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510641, PR China; School of Life Sciences and Medical Center, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, PR China.
Biomaterials. 2019 Sep;216:119248. doi: 10.1016/j.biomaterials.2019.119248. Epub 2019 Jun 7.
Neurodegenerative disorders such as Huntington's disease (HD) are fundamentally caused by accumulation of misfolded aggregate-prone proteins. Previous investigations have shown that these toxic protein aggregates could be degraded through autophagy induced by small molecules as well as by nanomaterials. However, whether engineered nanomaterials have the capacity to degrade these protein aggregates via the ubiquitin-proteasome system (UPS), the other major pathway for intracellular protein turnover, was unknown. Herein, we have synthesized biocompatible MnFeO nanoparticles (NPs) and demonstrated their unique effect in accelerating the clearance of mutant huntingtin (Htt) protein exhibiting 74 glutamine repeats [Htt(Q74)]. UPS, rather than autophagy, was responsible for the efficient Htt(Q74) degradation facilitated by MnFeO NPs. Meanwhile, we demonstrated that MnFeO NPs enhanced K48-linked ubiquitination of GFP-Htt(Q74). Moreover, ubiqinlin-1, but not p62/SQSTM1, served as the ubiquitin receptor that mediated the enhanced degradation of Htt(Q74) by MnFeO NPs. Our findings may have implications for developing novel nanomedicine for the therapy of HD and other polyglutamine expansion diseases.
神经退行性疾病，如亨廷顿病（HD），其根本原因是错误折叠的易于聚集的蛋白质的积累。先前的研究表明，这些毒性蛋白聚集体可以通过小分子以及纳米材料诱导的自噬来降解。然而，工程纳米材料是否有能力通过泛素-蛋白酶体系统（UPS）降解这些蛋白聚集体，UPS 是细胞内蛋白周转的另一个主要途径，这一点尚不清楚。在此，我们合成了具有生物相容性的 MnFeO 纳米颗粒（NPs），并证明了它们在加速清除具有 74 个谷氨酰胺重复的突变亨廷顿蛋白（Htt）[Htt（Q74）]方面的独特作用。UPS 而不是自噬，负责 MnFeO NPs 促进 Htt（Q74）的有效降解。同时，我们证明 MnFeO NPs 增强了 GFP-Htt（Q74）的 K48 连接泛素化。此外，泛素结合酶 1（ubiqilin-1）而不是 p62/SQSTM1 作为泛素受体，介导了 MnFeO NPs 增强 Htt（Q74）的降解。我们的发现可能对开发用于治疗 HD 和其他多谷氨酰胺扩展疾病的新型纳米医学具有重要意义。
