O‐GlcNAcylation of TDP‐43 suppresses proteinopathies and promotes TDP‐43's mRNA splicing activity. (15th April 2021)

• Record Type: Journal Article
• Authors: Zhao, Meng‐Jie; Yao, Xiao; Wei, Ping; Zhao, Chen; Cheng, Meng; Zhang, Dong; Xue, Wen; He, Wen‐Tian; Xue, Weili; Zuo, Xinxin; Jiang, Lei‐Lei; Luo, Zhiyuan; Song, Jiaqi; Shu, Wen‐Jie; Yuan, Han‐Ye; Liang, Yi; Sun, Hui; Zhou, Yan; Zhou, Yu; Zheng, Ling; Hu, Hong‐Yu; Wang, Jiwu; Du, Hai‐Ning
• Is Part Of: EMBO reports. Volume 22:Number 6(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-04-15
• Subjects: neurodegeneration -- O‐GlcNAcylation -- RNA splicing -- TDP‐43; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202051649
• Languages: English
• ISSNs: 1469-221X

Abstract

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. SYNOPSIS: O‐GlcNAcylation of TDP‐43 suppresses TDP‐43 proteinophathies and promotes TDP‐43's mRNA splicing activity, with potential implications for ALS/FTLD pathogenesis. TDP‐43 can be O‐GlcNAcylated by the enzyme OGT in vitro and in vivo, and O‐GlcNAcylation of TDP‐43 suppresses protein aggregation and hyperphosphorylation. TDP‐43 O‐GlcNAcylation affects the locomotion and longevity of Drosophila . O‐GlcNAcylation of TDP‐43 prevents aberrant splicing of key neuron genes, such as STMN2, Dnajc5, and Sort1 . Abstract : O‐GlcNAcylation of TDP‐43 suppresses TDP‐43 proteinophathies and promotes TDP‐43's mRNA splicing activity, with potential implications for ALS/FTLD pathogenesis.