TDP-43 Overexpression Induces Cellular Dysfunction and ALS-Associated Transcriptional Changes

Utilizing this system, we found that TDP-43 overexpression reflected key features associated with ALS pathology, causing cytotoxicity, nucleocytoplasmic mislocalization, and extensive transcriptomic changes. Furthermore, comparative RNA-seq analysis between this model and ALS patient-derived data revealed substantial overlaps, where 64% of the differentially expressed genes in the TDP-43 overexpression cell line were also found to be altered in ALS patient tissue, supporting the disease relevance of the model.

Genes of interest identified in the analysis included NUP85, SREBF2, VAMP5, WDR41, CDC23, DKC1, and PTS. This stable, inducible TDP-43 overexpression model and its associated transcriptomic dataset provide a versatile platform for ALS and other TDP-43 proteinopathy research, enabling the investigation of molecular drivers of TDP-43 dysfunction, the identification of potential disease-relevant pharmacological targets, and the evaluation of therapeutic candidates aimed at mitigating TDP-43 driven cytotoxicity or restoring normal TDP-43 localization.