Altered GM1 catabolism affects NMDAR-mediated Ca2+ signaling at ER-PM junctions and increases synaptic spineformation

Weesner, J. A.; Annunziata, I.; van de Vlekkert, D.; Robinson, C. G.; Campos, Y.; Mishra, A.; Fremuth, L. E.; Gomero, E.; Hu, H.; d'Azzo, A.

doi:10.1101/2023.07.10.548446

bioRxiv · 10.1101/2023.07.10.548446

Altered GM1 catabolism affects NMDAR-mediated Ca2+ signaling at ER-PM junctions and increases synaptic spineformation

Weesner, J. A.·Annunziata, I.·van de Vlekkert, D.·Robinson, C. G.·Campos, Y.·Mishra, A.·Fremuth, L. E.·Gomero, E.·Hu, H.·d'Azzo, A.

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Abstract

Endoplasmic reticulum-plasma membrane (ER-PM) junctions mediate Ca2+ flux across neuronal membranes. The properties of these membrane contact sites are defined by their lipid content, but little attention has been given to glycosphingolipids (GSLs). Here, we show that GM1-ganglioside, an abundant GSL in neuronal membranes, is integral to ER-PM junctions; it interacts with synaptic proteins/receptors and regulates Ca2+ signaling. In a model of the neurodegenerative lysosomal storage disease, GM1-gangliosidosis, pathogenic accumulation of GM1 at ER-PM junctions due to {beta}-galactosidase deficiency drastically alters neuronal Ca2+ homeostasis. Mechanistically, we show that GM1 interacts with the phosphorylated NMDAR Ca2+ channel, thereby increasing Ca2+ flux, activating ERK signaling, and increasing the number of synaptic spines without increasing synaptic connectivity. Thus, GM1 clustering at ER-PM junctions alters synaptic plasticity and exacerbates the generalized neuronal cell death characteristic of GM1-gangliosidosis.

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Weesner, J. A., Annunziata, I., van de Vlekkert, D., Robinson, C. G., Campos, Y., Mishra, A., Fremuth, L. E., Gomero, E., Hu, H., d'Azzo, A.. 2023-07-11. Altered GM1 catabolism affects NMDAR-mediated Ca2+ signaling at ER-PM junctions and increases synaptic spineformation. https://doi.org/10.1101/2023.07.10.548446

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