Therapeutic Horizons for the Clearance of TDP-43 Cellular Aggregates

The cytoplasmic accumulation of TDP-43 aggregates remains a persistent pathological hallmark of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic predominant age-related TDP-43 encephalopathy. The cell’s natural clearance mechanisms, the Ubiquitin-Proteasome System (UPS) and the autophagy-lysosome pathway (ALP), frequently fail due to a ‘vicious cycle’ created by the sequestration of essential downstream components by aberrant TDP-43, which interrupts autophagic flux. Classical autophagic activators (e.g., rapamycin) often initiate the pathway but cannot address downstream bottlenecks due to flux failure. This review revisits classical strategies and discusses newer approaches to modulate TDP-43 clearance, including TFEB activators, PROTACs (proteolysis-targeting chimeras), and antisense oligonucleotides (ASOs). We propose that adopting multi-targeting strategies and developing better biomarkers are vital for clinical success.