E3 ubiquitin ligases in neurodegenerative diseases

Duan Lu Hou; Josephine Ho; Tuchen Guan; Xiao-Xue Dong; Li Zeng; Laurie H Sanders; Yun-Cheng Wu; Eng King Tan; Zhi Dong Zhou

doi:10.1016/j.mmr.2026.100032

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E3 ubiquitin ligases in neurodegenerative diseases

REVIEW | Updated：2026-05-11

- E3 ubiquitin ligases in neurodegenerative diseases
- Military Medical Research (2026)
- Affiliations：
  
  National Neuroscience Institute, Singapore 308433, Singapore
  Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
  Nanyang Technological University, Singapore 639798, Singapore
  Departments of Neurology and Pathology, Duke University School of Medicine, Durham, NC 27710, USA
  Duke Center for Neurodegeneration and Neurotherapeutics, Duke University, Durham, NC 27710, USA
  Department of Neurology, Singapore General Hospital, Singapore 169608, Singapore
- Author bio：
  
  Yun-Cheng Wu, yunchw@medmail.com.cn
  Eng King Tan, Tan.eng.king@sgh.com.sg;
  *Zhi Dong Zhou, zhidong.zhou@duke-nus.edu.sg;
- Funds：
- DOI：10.1016/j.mmr.2026.100032
  CLC：
- Received：13 October 2025，
  
  Accepted：03 April 2026，
  
  Published：2026-04
- Accepted：
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Hou DL, Ho J, Guan T, Dong XX, Zeng L, Sanders LH, et al. E3 ubiquitin ligases in neurodegenerative diseases. Mil Med Res. 2026;13(1):100032.
DOI：

Hou DL, Ho J, Guan T, Dong XX, Zeng L, Sanders LH, et al. E3 ubiquitin ligases in neurodegenerative diseases. Mil Med Res. 2026;13(1):100032. DOI： 10.1016/j.mmr.2026.100032.

摘要

Abstract

Neurodegenerative diseases (NDs) are characterized by progressive neuronal loss and proteostatic failure

driven by impaired clearance of misfolded proteins via the ubiquitin-proteasome system (UPS) and autophagy. In UPS

E3 ubiquitin ligases are crucial for regulating protein ubiquitination and degradation. Mutations in E3 ligases

along with dysfunctions of specific ligases such as Parkin

the C-terminus of HSC70-interacting protein (CHIP)

and tripartite motif-containing proteins

have been identified as key factors in the buildup of amyloid-β

α-synuclein

tau

transactive response DNA-binding protein 43

and mutant huntingtin. These accumulations are associated with NDs like Parkinson’s disease

Alzheimer’s disease

Huntington’s disease

and amyotrophic lateral sclerosis. Therapeutic strategies targeting E3 ligases

particularly proteolysis-targeting chimeras (PROTACs)

are being developed for ND treatment and are currently in clinical trials. These approaches aim to enhance E3 ligase activity and promote selective protein degradation. Here

we examine how individual E3 ligases influence cell-fate decisions in NDs

showing that their substrate selection determines whether neurons survive or die. Building on this knowledge

we present an innovative therapeutic pipeline that includes ligase activators

PROTAC degraders

and miRNA switches

which are molecules designed to transition from research to clinical application.

关键词

Keywords

references

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