SQSTM1-mediated clearance of cytoplasmic mutant TARDBP/TDP-43 in the monkey brain
| Autor: | Yin, Peng, Bai, Dazhang, Deng, Fuyu, Zhang, Chen, Jia, Qingqing, Zhu, Longhong, Chen, Laiqiang, Li, Bang, Guo, Xiangyu, Ye, Jianmeng, Tan, Zhiqiang, Wang, Lu, Li, Shihua, Li, Xiao-Jiang |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Autophagy |
| ISSN: | 1554-8635 1554-8627 |
| DOI: | 10.1080/15548627.2021.2013653 |
| Popis: | The cytoplasmic accumulation and aggregates of TARDBP/TDP-43 (TAR DNA binding protein) are a pathological hallmark in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We previously reported that the primate specific cleavage of TARDBP accounts for its cytoplasmic mislocalization in the primate brains, prompting us to further investigate how the cytoplasmic TARDBP mediates neuropathology. Here we reported that cytoplasmic mutant TARDBP reduced SQSTM1 expression selectively in the monkey brain, when compared with the mouse brain, by inducing SQSTM1 mRNA instability via its binding to the unique 3ʹUTR sequence (GU/UG)n of the primate SQSTM1 transcript. Overexpression of SQSTM1 could diminish the cytoplasmic C-terminal TARDBP accumulation in the monkey brain by augmenting macroautophagy/autophagy activity. Our findings provide additional clues for the pathogenesis of cytoplasmic TARDBP and a potential therapy for mutant TARDBP-mediated neuropathology. |
| Databáze: | OpenAIRE |
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