期刊
FRONTIERS IN PHARMACOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2021.741219
关键词
autophagy; SC75741; TDP43; TDP25; c-Abl; ALS; TFEB
资金
- National Key R&D Program of China
The study demonstrates that SC75741 exerts neuroprotective effects on ALS through multiple mechanisms such as inhibiting NF-κB, enhancing TFEB nuclear translocation, and promoting TDP25 degradation. Additionally, the dual-targeted inhibition of c-Abl and NF-κB by SC75741 may be a potential therapeutic approach for TDP43 proteinopathies and ALS.
Abnormal accumulation of TDP43-related mutant proteins in the cytoplasm causes amyotrophic lateral sclerosis (ALS). Herein, unbiased drug screening approaches showed that SC75741, a multi-target inhibitor, inhibited inflammation-induced aggregation by inhibiting NF-kappa B and also degraded already aggregated proteins by inhibiting c-Abl mediated autophagy-lysosomal pathway. We delineate the mechanism that SC75741 could markedly enhance TFEB nuclear translocation by an mTORC1-independent TFEB regulatory pathway. In addition, SC75741 enhanced the interaction between p62 with TDP25 and LC3C, thus promoting TDP25 degradation. Taken together, these findings show that SC75741 has beneficial neuroprotective effects in ALS. Our study elucidates that dual-targeted inhibition of c-Abl and NF-kappa B may be a potential treatment for TDP43 proteinopathies and ALS.
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