TDP-43 toxic gain of function links ALS, FTD and Alzheimers Disease through splicing dysregulation

Cytoplasmic TDP-43 gain-of-function causes splicing abnormalities linked to ALS, FTLD, and AD, including APP isoform disruption, across all three diseases.

• Why it matters: Understanding TDP-43's role in neurodegeneration is crucial because its pathology is common in ALS, FTLD, and AD, yet its functional impact remains unclear, hindering targeted therapies.
• What they did: The study identified a conserved TDP-43-dependent splicing signature in AD, showing that cytoplasmic TDP-43 sequesters RNA-binding proteins, leading to disease-relevant mis-splicing in AD, ALS, and FTLD.
• The result: Findings suggest cytoplasmic TDP-43-driven splicing dysfunction as a shared neurodegenerative mechanism, linking AD with ALS/FTLD through splicing factor sequestration and APP isoform imbalance.