950-UBQLN2 Links Proteostasis in Neurodegeneration

This research identifies the protein UBQLN2 as a vital bridge between protein quality control and lipid metabolism in neurodegenerative diseases like ALS and FTD. By studying mutated neurons and brain organoids, scientists discovered that UBQLN2 normally regulates the breakdown of two enzymes, ILVBL and ALDH3A2, which are essential for processing fats during energy stress. When UBQLN2 is mutated or obstructed by TDP-43 protein aggregates, these enzymes accumulate, leading to lipid droplet depletion and excessive fatty acid oxidation that starves and kills neurons. Experimental treatments that reduced these enzyme levels or provided cholesterol supplements successfully restored metabolic balance and improved survival in animal models. Ultimately, the study establishes the UBQLN2–ILVBL/ALDH3A2 axis as a potential therapeutic target to prevent the metabolic collapse associated with dementia and motor neuron loss.
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Liu Y, Huang Z, Hsu Y W, et al. UBQLN2 links proteotoxicity with lipid metabolism in neurodegeneration[J]. Nature Neuroscience, 2026: 1-14.

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