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

Li Zhang; Peng-Fei Wei; Yong-Hong Song; Liang Dong; Ya-Dong Wu; Zong-Yao Hao; Song Fan; Sheng Tai; Jia-Lin Meng; Yang Lu; Jingzhe Xue; Chao-Zhao Liang; Long-Ping Wen

doi:10.1016/j.biomaterials.2019.119248

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

Biomaterials. 2019 Sep:216:119248. doi: 10.1016/j.biomaterials.2019.119248. Epub 2019 Jun 7.

Authors

Li Zhang¹, Peng-Fei Wei², Yong-Hong Song³, Liang Dong⁴, Ya-Dong Wu³, Zong-Yao Hao¹, Song Fan¹, Sheng Tai¹, Jia-Lin Meng¹, Yang Lu³, Jingzhe Xue⁵, Chao-Zhao Liang⁶, Long-Ping Wen⁷

Affiliations

¹ 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.
² 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.
³ School of Chemistry and Chemical Engineering, Hefei University of Technology, Hefei, Anhui, 230009, PR China.
⁴ Department of Chemistry, University of Science and Technology of China, Hefei, Anhui, 230026, PR China.
⁵ Department of Chemistry, University of Science and Technology of China, Hefei, Anhui, 230026, PR China. Electronic address: [email protected].
⁶ 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. Electronic address: [email protected].
⁷ 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. Electronic address: [email protected].

PMID: 31226569
DOI: 10.1016/j.biomaterials.2019.119248

Abstract

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.

Keywords: Autophagy-lysosomal pathway; Huntington's disease; MnFe(2)O(4) nanoparticles; Polyglutamine; Ubiquitin-proteasome system.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Ferric Compounds / chemistry
Ferric Compounds / pharmacology*
Huntingtin Protein / genetics
Huntingtin Protein / metabolism*
Huntington Disease / genetics
Huntington Disease / metabolism
Huntington Disease / therapy
Manganese Compounds / chemistry
Manganese Compounds / pharmacology*
Mice
Nanoparticles* / chemistry
Point Mutation
Proteasome Endopeptidase Complex / metabolism*
Ubiquitin / metabolism*
Ubiquitination

Substances

Ferric Compounds
Huntingtin Protein
Manganese Compounds
Ubiquitin
manganese ferrite
Proteasome Endopeptidase Complex