MassIVE MSV000093732

Partial Public PXD048152

UBQLN2 Governs Lipid Metabolism Linked to Neurodegeneration in ALS/FTD

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Description

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. [doi:10.25345/C5WM1448G] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: UBQLN2 ; ALS ; FTD ; frontotemporal dementia ; amyotrophic lateral sclerosis ; motor neuron ; dynamic SILAC ; dSILAC ; SILAC ; pSILAC

Contact

Principal Investigators:
(in alphabetical order) 		Ling Hao, The George Washington University, United States of America
Submitting User: haolab
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