2. Academic Validation
  3. O-GlcNAcylation of TDP-43 suppresses proteinopathies and promotes TDP-43's mRNA splicing activity

O-GlcNAcylation of TDP-43 suppresses proteinopathies and promotes TDP-43's mRNA splicing activity

  • EMBO Rep. 2021 Jun 4;22(6):e51649. doi: 10.15252/embr.202051649.
Meng-Jie Zhao  # 1,  Xiao Yao  # 2,  Ping Wei  # 3,  Chen Zhao  # 2,  Meng Cheng 2,  Dong Zhang 2,  Wen Xue 4 5,  Wen-Tian He 6,  Weili Xue 2,  Xinxin Zuo 2,  Lei-Lei Jiang 6,  Zhiyuan Luo 7,  Jiaqi Song 2,  Wen-Jie Shu 2,  Han-Ye Yuan 2,  Yi Liang 2,  Hui Sun 2,  Yan Zhou 7,  Yu Zhou 2,  Ling Zheng 2,  Hong-Yu Hu 6,  Jiwu Wang 4 5 8,  Hai-Ning Du 2
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Renmin Hospital of Wuhan University, College of Life Sciences, Wuhan University, Wuhan, China.
  • 2 Hubei Key Laboratory of Cell Homeostasis, RNA Institute, College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • 3 Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
  • 4 Clinical Research Institute, Affiliated Nanhua Hospital, University of South China, Hengyang, China.
  • 5 Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai, China.
  • 6 State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
  • 7 Frontier Science Center for Immunology and Metabolism, Medical Research Institute at School of Medicine, Wuhan University, Wuhan, China.
  • 8 Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • # Contributed equally.
PMID: 33855783 DOI: 10.15252/embr.202051649
Abstract

Pathological TDP-43 aggregation is characteristic of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP); however, how TDP-43 aggregation and function are regulated remain poorly understood. Here, we show that O-GlcNAc transferase OGT-mediated O-GlcNAcylation of TDP-43 suppresses ALS-associated proteinopathies and promotes TDP-43's splicing function. Biochemical and cell-based assays indicate that OGT's catalytic activity suppresses TDP-43 aggregation and hyperphosphorylation, whereas abolishment of TDP-43 O-GlcNAcylation impairs its RNA splicing activity. We further show that TDP-43 mutations in the O-GlcNAcylation sites improve locomotion defects of larvae and adult flies and extend adult life spans, following TDP-43 overexpression in Drosophila motor neurons. We finally demonstrate that O-GlcNAcylation of TDP-43 promotes proper splicing of many mRNAs, including STMN2, which is required for normal axonal outgrowth and regeneration. Our findings suggest that O-GlcNAcylation might be a target for the treatment of TDP-43-linked pathogenesis.

Keywords

O-GlcNAcylation; RNA splicing; TDP-43; neurodegeneration.

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