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UBQLN2 Governs Lipid Metabolism Linked to Neurodegeneration in ALS/FTD

ABSTRACT: Missense mutations in UBQLN2, a protein quality control factor, are associated with neurodegenerative diseases amyotrophic lateral sclerosis (ALS) overlapping with frontotemporal dementia (FTD). The mechanisms by which these mutations lead to neurodegeneration are not fully understood. Here we describe a critical role for UBQLN2 in regulating cellular lipid metabolism, which is crucial for cell survival under nutrient stress. The stress dependent regulation of lipid metabolism by UBQLN2 is mediated by ILVBL, a UBQLN2 substrate and a key enzyme in lipid turnover. The function of UBQLN2 in promoting ILVBL degradation and maintaining intracellular lipids was compromised by ALS/FTD-linked mutations in UBQLN2. As a result of the lipid dysregulation, synaptic vesicles were deficient and neuronal death was exacerbated in mutant UBQLN2 transgenic mice or human iPSCs derived motor neurons and cortical organoids. Replenishing lipids or restoring UBQLN2 function could reverse the deficits in the UBQLN2 mutant neurons under nutrient stress. Our study reveals UBQLN2 essential role in lipid metabolism and suggests metabolic imbalance underlying ALS/FTD and related neurodegenerative conditions.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Ling Hao

PROVIDER: MSV000093732 | MassIVE | Wed Dec 27 18:21:00 GMT 2023

SECONDARY ACCESSION(S): PXD048152

REPOSITORIES: MassIVE

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Project description:Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disorder, characterized by selective loss of motor neurons (MNs). A number of causative genetic mutations underlie the disease, including mutations in the fused in sarcoma (FUS) gene, which can lead to both juvenile and late onset ALS. Although ALS results from MN’s death, there is evidence that dysfunctional glial cells, including oligodendroglia, contribute to neurodegeneration. Here, we used human induced pluripotent stem cells (hiPSCs) with a FUSR521H or a FUSP525L mutation and their isogenic controls to generate oligodendrocyte progenitor cells (OPCs) by inducing SOX10 expression from a TET-On SOX10 cassette as described previously in our lab. Mutant and control iPSC differentiated efficiently into OPCs. RNA sequencing identified a myelin sheath-related phenotype in mutant OPCs. Subsequent lipidomics studies demonstrated defects in myelin lipids, with a reduction of phospholipids in mutant OPCs. Among them, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are the most two abundant phospholipid in mammalian cells and regulate the mitochondria-associated ER membrane (MAM) integrity. Interestingly, FUSR521H mutant OPCs displayed a decrease in the PC/PE ratio, known to be associated with maintaining membrane (mitochondria) integrity. Proximity ligation assay further indicated that MAM was diminished in mutant OPCs. Moreover, mutant OPCs displayed stronger activation of unfolded protein response markers, a hallmark of increased susceptibility to endoplasmic reticulum (ER) stress, when exposed to thapsigargin, and exhibited impaired mitochondrial respiration and reduced Ca2+ signaling from ER Ca2+ stores. Taken together, these results demonstrate that FUS mutant OPCs display defects in lipid metabolism associated with MAM disruption manifested by impaired mitochondrial metabolism with increased susceptibility to ER stress and suppressed physiological Ca2+ signaling events.

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UBQLN2 Governs Lipid Metabolism Linked to Neurodegeneration in ALS/FTD

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