Human iPSC Models of Ganglioside Deficiency Reveal a Sialylated Lipid Requirement for Plasma-Membrane Organization and Neuronal Activity
Barrow, H. G.; Han, Z. Z.; Nicholson, A. S.; Strasser, S.; Nash, D. A.; Suberu, J. O.; Antrobus, R.; te Vruchte, D.; Priestman, D. A.; Graham, S. C.; Platt, F. M.; Deane, J. E.
Show abstract
Gangliosides are abundant neuronal glycosphingolipids (GSL) whose precise roles in human neuronal function remain poorly defined. Loss of the ganglioside biosynthetic enzymes ST3GAL5 or B4GALNT1 causes severe neurodevelopmental disorders. Using isogenic human iPSC derived cortical neurons, we demonstrated that disruptions of either gene eliminated major neuronal gangliosides yet produced strikingly divergent phenotypic outcomes. ST3GAL5 loss reprogrammed the GSL repertoire, generating non-neuronal globo- and o-series lipids, and abolished network-level electrical activity. In contrast, B4GALNT1 deficient neurons retained almost normal electrical activity, supported by an accumulation of simple sialylated precursor GSLs (GM3/GD3). Proteomic profiling revealed that ST3GAL5 deficiency caused a severe reduction in plasma membrane (PM) protein abundance, including ion channels, GPCRs, and synaptic organizer proteins, while B4GALNT1 loss did not induce PM changes. These findings demonstrate that sialylated GSLs are essential scaffolds for PM organization and neuronal excitability, establishing a mechanistic basis for the severe phenotype caused by loss of the GM3 synthase ST3GAL5 and highlighting key species-specific features of human GSL metabolism.
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