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O‐GlcNAcylation of TDP‐43 suppresses proteinopathies and promotes TDP‐43’s mRNA splicing activity
Author(s) -
Zhao MengJie,
Yao Xiao,
Wei Ping,
Zhao Chen,
Cheng Meng,
Zhang Dong,
Xue Wen,
He WenTian,
Xue Weili,
Zuo Xinxin,
Jiang LeiLei,
Luo Zhiyuan,
Song Jiaqi,
Shu WenJie,
Yuan HanYe,
Liang Yi,
Sun Hui,
Zhou Yan,
Zhou Yu,
Zheng Ling,
Hu HongYu,
Wang Jiwu,
Du HaiNing
Publication year - 2021
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202051649
Subject(s) - china , medicine , chinese academy of sciences , library science , gerontology , political science , computer science , law
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.