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

## TL;DR

This paper reviews strategies to restore autophagy for clearing TDP-43 aggregates in neurodegenerative diseases like ALS and FTD.

## Contribution

The paper proposes multi-targeting strategies and better biomarkers to improve TDP-43 clearance therapies.

## Key findings

- Classical autophagic activators like rapamycin fail to resolve downstream clearance issues of TDP-43 aggregates.
- Newer approaches such as TFEB activators, PROTACs, and ASOs offer potential for improved TDP-43 clearance.
- Multi-targeting strategies and better biomarkers are essential for successful clinical interventions.

## Abstract

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.