# TDP-43 impairs glycolysis by sequestering hexokinase 1 in amyotrophic lateral sclerosis

## TL;DR

This paper shows that TDP-43 in ALS disrupts glycolysis by trapping HK1, causing energy problems in neurons and suggesting glycolytic restoration as a treatment.

## Contribution

The study reveals a novel mechanism where TDP-43 impairs glycolysis by sequestering HK1, linking metabolic dysfunction to ALS pathology.

## Key findings

- Cytoplasmic TDP-43 reduces glycolytic capacity in patient-derived neurons by binding and sequestering HK1.
- Compensating for HK1 loss improves motor performance and survival in TDP-43-associated ALS models.
- TDP-43 mislocalization decreases HK1 mitochondrial association and enzymatic activity in multiple ALS models.

## Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration and cytoplasmic mislocalization of TDP-43. While metabolic dysfunction is increasingly recognized in ALS, the mechanistic link between impaired energy metabolism and TDP-43 pathology remains unknown. Here, we show that cytoplasmic TDP-43 directly disrupts glycolysis by targeting hexokinase 1 (HK1), the first rate-limiting enzyme of the pathway. In cells expressing a TDP-43 variant lacking its nuclear localization signal and in patient-derived iPSC motor neurons, TDP-43 accumulation in the cytoplasm reduces glycolytic capacity, indicating a neuron-intrinsic metabolic defect. Across cellular models including patient-derived neurons, TDP-43 mutant mice, and postmortem spinal cord tissue from ALS patients, we observe consistent decreases in HK1 protein level, mitochondrial association, and enzymatic activity, despite unchanged transcript levels. Mechanistically, cytoplasmic TDP-43 directly binds to HK1, disassociating it from mitochondria and promoting its sequestration into insoluble aggregates. This mislocalization impairs glycolysis and increases neuronal vulnerability. Notably, compensation for HK1 loss reduces cytoplasmic TDP-43 and ubiquitin accumulation, improves motor performance, and prolongs survival in TDP-43–associated ALS models. Together, these findings identify a previously unrecognized mechanism by which TDP-43 impairs glycolysis through HK1 misregulation and highlight glycolytic restoration as a potential therapeutic strategy in ALS.

The online version contains supplementary material available at 10.1007/s00401-026-02996-6.