| Autor: |
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 |
| Zdroj: |
Cell Reports; May2024, Vol. 43 Issue 5, pN.PAG-N.PAG, 1p |
| Abstrakt: |
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 β-galactosidase deficiency drastically alters neuronal Ca2+ homeostasis. Mechanistically, we show that GM1 interacts with the phosphorylated N-methyl D-aspartate receptor (NMDAR) Ca2+ channel, thereby increasing Ca2+ 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. [Display omitted] • Neuronal accumulation of GM1 due to β-GAL deficiency increases ER-PM junction formation • GM1 binds pNMDAR at the ER-PM junctions, altering intracellular Ca2+ concentration • pNMDAR-mediated Ca2+ signaling and increased BDNF levels activate the ERK pathway • Altered levels of GM1 increase synaptic spine formation without increasing connectivity Weesner et al. find that, in GM1-gangliosidosis mice, neuronal accumulation of GM1 at the ER-PM junctions alters NMDAR-mediated Ca2+ signaling and activates the synaptogenesis pathway via ERK signaling. This leads to increased synaptic spine density without an increase in synaptic connectivity, contributing to the neurodegeneration characteristic of the disease. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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