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UBQLN2 Links Proteotoxicity with Lipid Metabolism in Neurodegeneration

A new Nature Neuroscience study reveals that the ubiquitin‑binding protein UBQLN2 directly connects proteotoxic stress with lipid metabolism in ALS and frontotemporal dementia (FTD). Using CRISPR‑edited iPSC‑derived motor neurons, the authors show that disease‑linked UBQLN2 mutations dramatically slow protein turnover and disrupt lipid droplet homeostasis, especially under glucose deprivation. The mutations trigger over‑activation of long‑chain fatty‑acid oxidation, deplete cholesterol, and impair synaptic vesicle integrity, leading to neuronal loss. Rescue experiments identify ILVBL and ALDH3A2 as UBQLN2 client enzymes and demonstrate that modest cholesterol supplementation restores viability.