Altered GM1 catabolism affects NMDAR-mediated Ca 2+ signaling at ER-PM junctions and increases synaptic spine formation in a GM1-gangliosidosis model

• Published in: Cell reports (Cambridge) Vol. 43; no. 5; p. 114117
• Main Authors: Weesner, Jason A, Annunziata, Ida, van de Vlekkert, Diantha, Robinson, Camenzind G, Campos, Yvan, Mishra, Ashutosh, Fremuth, Leigh E, Gomero, Elida, Hu, Huimin, d'Azzo, Alessandra
• Format: Journal Article
• Language: English
• Published: United States 28.05.2024
• Subjects: Animals; Calcium - metabolism; Calcium Signaling; Cell Membrane - metabolism; Dendritic Spines - metabolism; Disease Models, Animal; Endoplasmic Reticulum - metabolism; Female; G(M1) Ganglioside - metabolism; Gangliosidosis, GM1 - metabolism; Gangliosidosis, GM1 - pathology; Humans; Male; Mice; Neuronal Plasticity; Neurons - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Synapses - metabolism; CP: Cell biology; CP: Neuroscience; lysosomal storage disease; membrane contact sites; NMDAR; synapse; GM1-gangliosidosis; dendritic spines; Ca(2+) signaling; ER-PM junctions
• ISSN: 2211-1247

Endoplasmic reticulum-plasma membrane (ER-PM) junctions mediate Ca 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 Ca signaling. In a model of the neurodegenerative lysosomal storage disease, GM1-gangliosidosis, pathogenic accumulation of GM1 at ER-PM junctions due to β-galactosidase deficiency drastically alters neuronal Ca homeostasis. Mechanistically, we show that GM1 interacts with the phosphorylated N-methyl D-aspartate receptor (NMDAR) Ca channel, thereby increasing Ca flux, activating extracellular signal-regulated kinase (ERK) signaling, and increasing the number of synaptic spines without increasing synaptic connectivity. Thus, GM1 clustering at ER-PM junctions alters synaptic plasticity and worsens the generalized neuronal cell death characteristic of GM1-gangliosidosis.