A quantitative cell-based reporter links TDP-43 aggregation and dysfunction to define pathogenic mechanisms - PubMed
6 hours ago
- #TDP-43
- #neurodegenerative diseases
- #protein aggregation
- TDP-43 pathology is linked to neurodegenerative disorders like ALS, FTD, and LATE.
- Cytoplasmic TDP-43 aggregates disrupt its nuclear function, leading to gene expression dysregulation.
- A new cell-based reporter captures TDP-43 aggregation and loss of function.
- Aggregation driven by prion-like seeding depletes nuclear TDP-43 and increases DNA damage and cryptic exon splicing.
- The seeding model helps study TDP-43 pathology mechanisms and identify aggregation modulators.
- Aggregate seeding disrupts TDP-43 autoregulation, creating a toxic feedback loop.
- Reducing ataxin-2 levels decreases TDP-43 aggregation and restores its activity.
- Findings suggest strategies to mitigate TDP-43 dysfunction and toxicity in disease.