筋萎縮性側索硬化症に対するアンチセンス核酸治療薬の可能性

抄録

Using antisense oligonucleotide (ASO) for familial amyotrophic lateral sclerosis (ALS) therapy has shown promise. However, therapy for sporadic ALS is more challenging since its pathogenesis is not fully understood. We aimed to better understand the role of TAR DNA–binding protein 43 (TDP–43) in ALS pathogenesis by developing a in silico model that simulates intracellular TDP–43 dynamics. There was a trade–off between the robustness of TDP–43 regulation, which depends on the redundancy of TDP–43 transcription, and vulnerability to the disease state. The transcriptional redundancy of TDP–43 contributes to TDP–43 autoregulation, which functions by nonsense–mediated mRNA decay via alternative splicing. Alternative splicing is reduced by ALS–associated TDP–43 mutations, motor cortex aging, and nuclear TDP–43 reduction. Therefore, the alternative splicing of TDP–43 may be a promising ASO target for ALS therapy.