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ALDOA Promotes Glycolysis and NLRP3/GSDMD Pyroptosis to Accelerate ALS Progression
Kaixin Yan1, Yan Jiang1, Yuxuan Yong1
1Department of Neurology, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
Annals of Clinical and Translational Neurology
|March 24, 2026
Summary
Aldolase A (ALDOA) drives amyotrophic lateral sclerosis (ALS) progression by promoting motor neuron pyroptosis via glycolysis. Inhibiting ALDOA reduces this process, offering a potential therapeutic strategy for ALS.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Amyotrophic lateral sclerosis (ALS) involves motor neuron degeneration.
- Glycolytic dysregulation is linked to ALS progression, but mechanisms are unclear.
Purpose of the Study:
- Investigate Aldolase A's (ALDOA) role in ALS progression.
- Examine ALDOA's mechanism in glycolysis-mediated motor neuron pyroptosis.
Main Methods:
- Used TDP-43 cKO mice and TDP-43 KO NSC34 cells.
- Assessed motor function, L-lactic acid, ALDOA/NLRP3/GSDMD expression, and cell viability.
- Administered ALDOA inhibitor Aldometanib.
Main Results:
- ALS models showed motor deficits, weight loss, and reduced survival.
- Elevated ALDOA, L-lactic acid, and NLRP3/GSDMD inflammasome activation observed in motor cortex.
- Aldometanib suppressed glycolysis, prolonged survival, and inhibited pyroptosis.
Conclusions:
- ALDOA-driven glycolysis activates the NLRP3/GSDMD inflammasome, causing motor neuron pyroptosis.
- ALDOA inhibition alleviates glycolytic dysregulation and extends survival.
- ALDOA is identified as a potential therapeutic target for ALS.
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