GFAP mutants cause imbalance of selective lipid classes in a cellular model of Alexander disease
Abstract
Alexander disease (AxD) is a rare neurodegenerative disorder caused by mutations in glial fibrillary acidic protein (GFAP), primarily affecting astrocytes. Although these mutations alter astrocyte structure and metabolism, their impact on the lipidome remains understudied. Here, wild-type GFP-GFAP and AxD-associated mutants (R239C, R239G, R79C, and E373K) were expressed in U-87 MG astrocytoma cells to evaluate GFAP organization through confocal microscopy and lipidomic alterations quantified by mass spectrometry. Membrane fluidity and lipid storage were complementarily assessed. Expression of AxD-associated GFAP mutants induced distinct lipidomic alterations, with R239C eliciting the most pronounced changes, including enrichment of sphingomyelins, trihexosylceramides, acylcarnitines, triglycerides, cholesteryl esters, and ether-linked lipids. These alterations suggest adaptive mechanisms to preserve membrane integrity, lipid raft organization, bioenergetics, redox homeostasis, and cell survival. Overall, in the AxD astrocytoma cell model, different GFAP mutations induce extensive and non-overlapping remodeling of lipids involved in membrane structure and organization, antioxidant defense, and bioenergetic pathways.
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BibTeX
@article{fernandezbernal2026gfap,
title = {{GFAP mutants cause imbalance of selective lipid classes in a cellular model of Alexander disease}},
author = {Anna Fernàndez-Bernal and Nuria Goya-Iglesias and Idoia Company-Marin and Natàlia Mota-Martorell and Marcela Pekna and Milos Pekny and Joaquim Sol and Èlia Obis and Reinald Pamplona and María A. Pajares and Dolores Pérez-Sala and Mariona Jové},
journal = {iScience},
year = {2026},
month = oct,
doi = {10.1016/j.isci.2026.117903},
url = {https://www.cell.com/iscience/fulltext/S2589-0042(26)03286-4},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - GFAP mutants cause imbalance of selective lipid classes in a cellular model of Alexander disease
AU - Anna Fernàndez-Bernal
AU - Nuria Goya-Iglesias
AU - Idoia Company-Marin
AU - Natàlia Mota-Martorell
AU - Marcela Pekna
AU - Milos Pekny
AU - Joaquim Sol
AU - Èlia Obis
AU - Reinald Pamplona
AU - María A. Pajares
AU - Dolores Pérez-Sala
AU - Mariona Jové
PY - 2026
DA - 2026/10/20
JO - iScience
DO - 10.1016/j.isci.2026.117903
UR - https://www.cell.com/iscience/fulltext/S2589-0042(26)03286-4
AB - Alexander disease (AxD) is a rare neurodegenerative disorder caused by mutations in glial fibrillary acidic protein (GFAP), primarily affecting astrocytes. Although these mutations alter astrocyte structure and metabolism, their impact on the lipidome remains understudied. Here, wild-type GFP-GFAP and AxD-associated mutants (R239C, R239G, R79C, and E373K) were expressed in U-87 MG astrocytoma cells to evaluate GFAP organization through confocal microscopy and lipidomic alterations quantified by mass spectrometry. Membrane fluidity and lipid storage were complementarily assessed. Expression of AxD-associated GFAP mutants induced distinct lipidomic alterations, with R239C eliciting the most pronounced changes, including enrichment of sphingomyelins, trihexosylceramides, acylcarnitines, triglycerides, cholesteryl esters, and ether-linked lipids. These alterations suggest adaptive mechanisms to preserve membrane integrity, lipid raft organization, bioenergetics, redox homeostasis, and cell survival. Overall, in the AxD astrocytoma cell model, different GFAP mutations induce extensive and non-overlapping remodeling of lipids involved in membrane structure and organization, antioxidant defense, and bioenergetic pathways.
SN - 2589-0042
ER -