Comprehensive Transcriptomic Analysis of NSC34 Motor Neurons following TDP43 Modulation: Knockdown vs. Control and Wild Type vs. TDP43 M337V Mutation

This investigation delves into the intricate molecular mechanisms underpinning the convergence of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), both neurodegenerative disorders characterized by shared clinical, pathological, and genetic features. Central to our study is the TAR DNA binding protein 43 kDa (TDP-43), a key constituent identified in pathological protein aggregates prevalent in both familial and sporadic cases of ALS and FTLD. Our experimental design employs NSC34 motor neurons, a cellular model, to mimic TDP-43 loss of function through the application of RNA interference (RNAi) to downregulate TDP-43 expression in NSC34 cells. Additionally, we introduced the TDP-43 M337V mutant to emulate observed TDP-43 mutations, thereby recapitulating essential aspects of ALS and FTLD pathology, including the selective necroptosis of motor neurons. A distinctive facet of our investigation lies in the adoption of a novel transcriptomic approach, acknowledging the multifaceted role of TDP43 in cellular processes such as metabolism, RNA processing, and transcription. By profiling both coding and noncoding RNA, our aim is to comprehensively unravel the intricate impact of TDP43 proteinopathy on the entire transcriptome. Leveraging next-generation sequencing, we scrutinize how TDP-43 loss of function and aggregation dynamically shape the gene expression landscape. This nuanced strategy significantly enhances our understanding of the intricate interplay between TDP43 dysfunction and the transcriptomic milieu, providing valuable insights into the pathogenesis of ALS and FTLD.