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Altered GM1 catabolism affects NMDAR-mediated Ca²⁺ signaling at ER-PM junctions and increases synaptic spine formation in a GM1-gangliosidosis model.

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 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.

SUBMITTER: Weesner JA

PROVIDER: S-EPMC11244331 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature

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Altered GM1 catabolism affects NMDAR-mediated Ca2+ signaling at ER-PM junctions and increases synaptic spine formation in a GM1-gangliosidosis model.

Weesner Jason A JA Annunziata Ida I van de Vlekkert Diantha D Robinson Camenzind G CG Campos Yvan Y Mishra Ashutosh A Fremuth Leigh E LE Gomero Elida E Hu Huimin H d'Azzo Alessandra A

Cell reports 20240416 5

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 ...[more]

PMID: 38630590

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Project description:IntroductionGM1 gangliosidosis is a rare autosomal recessive genetic disorder caused by the disruption of the GLB1 gene that encodes β-galactosidase, a lysosomal hydrolase that removes β-linked galactose from the non-reducing end of glycans. Deficiency of this catabolic enzyme leads to the lysosomal accumulation of GM1 and its asialo derivative GA1 in β-galactosidase deficient patients and animal models. In addition to GM1 and GA1, there are other glycoconjugates that contain β-linked galactose whose metabolites are substrates for β-galactosidase. For example, a number of N-linked glycan structures that have galactose at their non-reducing end have been shown to accumulate in GM1 gangliosidosis patient tissues and biological fluids.ObjectiveIn this study, we attempt to fully characterize the broad array of GLB1 substrates that require GLB1 for their lysosomal turnover.ResultsUsing tandem mass spectrometry and glycan reductive isotope labeling with data-dependent mass spectrometry, we have confirmed the accumulation of glycolipids (GM1 and GA1) and N-linked glycans with terminal beta-linked galactose. We have also discovered a novel set of core 1 and 2 O-linked glycan metabolites, many of which are part of structurally-related isobaric series that accumulate in disease. In the brain of GLB1 null mice, the levels of these glycan metabolites increased along with those of both GM1 and GA1 as a function of age. In addition to brain tissue, we found elevated levels of both N-linked and O-linked glycan metabolites in a number of peripheral tissues and in urine. Both brain and urine samples from human GM1 gangliosidosis patients exhibited large increases in steady state levels for the same glycan metabolites, demonstrating their correlation with this disease in humans as well.ConclusionsOur studies illustrate that GLB1 deficiency is not purely a ganglioside accumulation disorder, but instead a broad oligosaccharidosis that include representatives of many β-linked galactose containing glycans and glycoconjugates including glycolipids, N-linked glycans, and various O-linked glycans. Accounting for all β-galactosidase substrates that accumulate when this enzyme is deficient increases our understanding of this severe disorder by identifying metabolites that may drive certain aspects of the disease and may also serve as informative disease biomarkers to fully evaluate the efficacy of future therapies.

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Altered GM1 catabolism affects NMDAR-mediated Ca²⁺ signaling at ER-PM junctions and increases synaptic spine formation in a GM1-gangliosidosis model.

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

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Altered GM1 catabolism affects NMDAR-mediated Ca2+ signaling at ER-PM junctions and increases synaptic spine formation in a GM1-gangliosidosis model.

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Altered GM1 catabolism affects NMDAR-mediated Ca&lt;sup&gt;2+&lt;/sup&gt; signaling at ER-PM junctions and increases synaptic spine formation in a GM1-gangliosidosis model.

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OmicsDI is part of the ELIXIR infrastructure

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Altered GM1 catabolism affects NMDAR-mediated Ca²⁺ signaling at ER-PM junctions and increases synaptic spine formation in a GM1-gangliosidosis model.

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