DataSheet1_SC75741, A Novel c-Abl Inhibitor, Promotes the Clearance of TDP25 Aggregates via ATG5-Dependent Autophagy Pathway.pdf

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-κB 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-κB may be a potential treatment for TDP43 proteinopathies and ALS.

细胞质中TDP43相关突变蛋白的异常蓄积可引发肌萎缩侧索硬化症（amyotrophic lateral sclerosis，ALS）。本研究采用无偏倚药物筛选策略发现，多靶点抑制剂SC75741可通过抑制核因子κB（NF-κB）通路抑制炎症诱导的蛋白聚集，同时通过抑制c-Abl介导的自噬溶酶体途径降解已形成的聚集蛋白。我们进一步阐明了SC75741的作用机制：其可通过不依赖于雷帕霉素复合物1（mTORC1）的TFEB调控通路，显著增强转录因子EB（TFEB）的核转位。此外，SC75741可增强p62蛋白与TDP25、LC3C之间的相互作用，进而促进TDP25的降解。综上，上述研究结果表明SC75741对ALS具有良好的神经保护作用。本研究证实，同时靶向抑制c-Abl与NF-κB，有望成为治疗TDP43蛋白病及ALS的潜在治疗策略。