UBQLN2 Links Proteotoxicity with Lipid Metabolism in Neurodegeneration

Protein homeostasis and lipid metabolism are crucial cellular processes that are dysregulated in neurodegeneration. However, their connection in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) remains unexplored. Ubiquilin 2 (UBQLN2) is a protein quality control factor linked to familial ALS/FTD and broader neurodegeneration. Here, we idetified UBQLN2 as an essential regulator for intracellular lipid metabolism, the biological processes of which are impaired by ALS/FTD-linked mutations in UBQLN2. Using transcriptome analysis, we profiled the molecular changes in motor neurons derived from isogenic control and UBQLN2-mutant iPSCs under ALS/FTD-associated metabolic stress, glucose deficiency. We found that biological processes related to cell survival and metabolism were greately affected by the disease-linked mutations in UBQLN2, suggesting that the impaired metabolic role of UBQLN2 by the disease-linked mutations is involved in the pathogenesis of relative neurodegeneration.