Chemical and Molecular Strategies in Restoring Autophagic Flux in TDP-43 Proteinopathy.

Jamerlan A, Hulme J

Molecules (Basel, Switzerland) 2026

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 (LATE). The cell's natural clearance mechanisms, the Ubiquitin-Proteasome System (UPS) and the autophagy-lysosome pathway (ALP), are hypothesized to fail, at least in part, due to the sequestration of key components of these pathways by pathological TDP-43 species, thereby impairing autophagosome-lysosome fusion and lysosomal competence. Classical autophagic activators (e.g., rapamycin) can initiate upstream steps in the pathway but cannot address downstream flux bottlenecks, limiting their ability to restore effective TDP-43 clearance. This review revisits classical strategies and discusses newer approaches to modulate TDP-43 clearance, including transcription factor EB (TFEB) activators, proteolysis-targeting chimeras (PROTACs), and antisense oligonucleotides (ASOs). We propose that adopting multi-targeting strategies and developing better biomarkers are vital for clinical success.

3 Figures Extracted

Figure 1 PMC

The vicious cycle of TDP-43-mediated proteostatic collapse. TDP-43 aggregates actively contribute to pathology rather than merely serving as passive m...

Figure 2 PMC

Nested metabolic hierarchy of therapeutic interventions of TDP-43 proteinopathy. The schematic illustrates the transition from broad metabolic regulat...

Figure 3 PMC

Shifting the paradigm from autophagy induction to flux restoration. Traditional therapeutic approaches often emphasize initiating autophagy, which can...