Withaferin-A, an active withanolide derived from the medicinal herbal plant Withania somnifera induces autophagy, reduces TDP-43 proteinopathy, and improves cognitive function in transgenic mice expressing mutant TDP-43 modelling FTLD. TDP-43 is a nuclear DNA/RNA-binding protein with cellular functions in RNA transcription and splicing. Abnormal cytoplasmic aggregates of TDP-43 occur in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). To date, no effective treatment is available for TDP-43 proteinopathies. Here, we tested the effects of withaferin-A (WFA), an active withanolide extracted from the medicinal herbal plant Withania somnifera, in a transgenic mouse model of FTLD expressing a genomic fragment encoding mutant TDP-43^G348C. WFA treatment ameliorated the cognitive performance of the TDP-43^G348C mice, and it reduced NF-κB activity and neuroinflammation in the brain. WFA alleviated TDP-43 pathology while it boosted the levels of the autophagic marker LC3BII in the brain. These data suggest that WFA and perhaps other autophagy inducers should be considered as potential therapy for neurodegenerative diseases with TDP-43 pathology.

Withaferin-A 是一种源自药用草本植物睡茄的活性睡茄内酯，可诱导自噬，减少 TDP-43 蛋白病，并改善表达突变 TDP-43 模型 FTLD 的转基因小鼠的认知功能。 TDP-43 是一种核 DNA/RNA 结合蛋白，具有 RNA 转录和剪接的细胞功能。 TDP-43 胞质异常聚集发生在多种神经退行性疾病中，包括肌萎缩侧索硬化症 (ALS)、额颞叶变性 (FTLD) 和边缘系统主导的年龄相关 TDP-43 脑病 (LATE)。迄今为止，尚无针对 TDP-43 蛋白病的有效治疗方法。在这里，我们在表达编码突变体 TDP-43 ^G348C的基因组片段的 FTLD 转基因小鼠模型中测试了睡茄素-A (WFA) 的作用，这是一种从药用草药植物睡茄中提取的活性睡茄内酯。 WFA 治疗改善了 TDP-43 ^G348C小鼠的认知表现，并减少了大脑中 NF-κB 的活性和神经炎症。 WFA 缓解了 TDP-43 病理，同时提高了大脑中自噬标记物 LC3BII 的水平。这些数据表明，WFA 和其他自噬诱导剂应被视为治疗具有 TDP-43 病理学的神经退行性疾病的潜在疗法。