MnFe2O4 nanoparticles accelerate the clearance of mutant huntingtin selectively through ubiquitin-proteasome system

• Published in: Biomaterials Vol. 216; p. 119248
• Main Authors: Zhang, Li, Wei, Peng-Fei, Song, Yong-Hong, Dong, Liang, Wu, Ya-Dong, Hao, Zong-Yao, Fan, Song, Tai, Sheng, Meng, Jia-Lin, Lu, Yang, Xue, Jingzhe, Liang, Chao-Zhao, Wen, Long-Ping
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.09.2019
• Subjects: autophagy; Autophagy-lysosomal pathway; glutamine; Huntington's disease; MnFe2O4 nanoparticles; mutants; nanomedicine; nanoparticles; neurodegenerative diseases; Polyglutamine; protein aggregates; therapeutics; toxicity; ubiquitin; Ubiquitin-proteasome system; ubiquitination; Polyglutamine; Huntington's disease; Ubiquitin-proteasome system; MnFe2O4 nanoparticles; Autophagy-lysosomal pathway
• ISSN: 0142-9612; 1878-5905; 1878-5905
• DOI: 10.1016/j.biomaterials.2019.119248

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 MnFe2O4 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 MnFe2O4 NPs. Meanwhile, we demonstrated that MnFe2O4 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 MnFe2O4 NPs. Our findings may have implications for developing novel nanomedicine for the therapy of HD and other polyglutamine expansion diseases.