Zhao, M.J., Yao, X., Wei, P., Zhao, C., Cheng, M., Zhang, D., Xue, W., He, W.T., Xue, W., Zuo, X., Jiang, L.L., Luo, Z., Song, J., Shu, W.J., Yuan, H.Y., Liang, Y., Sun, H., Zhou, Y., Zhou, Y., Zheng, L., Hu, H.Y., Wang, J., Du, H.N. (2021). O-GlcNAcylation of TDP-43 suppresses proteinopathies and promotes TDP-43's mRNA splicing activity.  EMBO Rep. 22(6): e51649.

FBrf0249184

Research paper

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.

PMC8183420 (PMC) (EuropePMC)