# From Evasion to Collapse: The Kinetic Cascade of TDP-43 and the Failure of Proteostasis

## TL;DR

This paper explains how TDP-43 protein misfolding and aggregation contribute to neurodegenerative diseases like ALS and FTD, and suggests new therapeutic strategies to target these processes.

## Contribution

The paper introduces a novel conceptual framework of a kinetic cascade linking TDP-43 misfolding, phase separation, and clearance failure.

## Key findings

- TDP-43 misfolding and phase separation lead to aggregation and clearance failure in ALS and FTD.
- Disruption of the ubiquitin-proteasome system and autophagy-lysosome pathway accelerates TDP-43 aggregation.
- Therapies should target kinetic inflection points like oligomer seeding and PTM modulation.

## Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases that, despite the availability of symptomatic and modestly beneficial treatments, still lack therapies capable of halting disease progression. A histopathological hallmark of both diseases is the cytoplasmic deposition of TDP-43 in neurons, which is attributed to both intrinsic (e.g., mutations, aberrant cleavage) and extrinsic factors (e.g., prolonged oxidative stress, impaired clearance pathways). Mutations and certain PTMs (e.g., cysteine oxidation) destabilize RNA binding, promoting monomer misfolding and increasing its half-life. Disruptions to core ubiquitin-proteasome system (UPS) subunits impede efficient processing, contributing to the clearance failure of misfolded TDP-43 monomers. The accumulation of monomers drives phase separation within stress granules, creating nucleation hotspots that eventually bypass the thermodynamic barrier, resulting in exponential growth. This rapid growth then culminates in the failure of the autophagy-lysosome pathway (ALP) to contain the aggregation, resulting in a self-sustaining feed-forward loop. Here, we organize these factors into a conceptual kinetic cascade that links TDP-43 misfolding, phase separation, and clearance failure. Therapeutic strategies must therefore move beyond simple clearance and focus on targeting these kinetic inflection points (e.g., oligomer seeding, PTM modulation).