Altered GM1 catabolism affects NMDAR-mediated Ca2+ signaling at ER-PM junctions and increases synaptic spine formation in a GM1-gangliosidosis model
Jason A. Weesner,
Ida Annunziata,
Diantha van de Vlekkert,
Camenzind G. Robinson,
Yvan Campos,
Ashutosh Mishra,
Leigh E. Fremuth,
Elida Gomero,
Huimin Hu,
Alessandra d’Azzo
Affiliations
Jason A. Weesner
St. Jude Children’s Research Hospital, Department of Genetics, Memphis, TN 38105, USA
Ida Annunziata
St. Jude Children’s Research Hospital, Department of Genetics, Memphis, TN 38105, USA; St. Jude Children’s Research Hospital, Compliance Office, Memphis, TN 38105, USA
Diantha van de Vlekkert
St. Jude Children’s Research Hospital, Department of Genetics, Memphis, TN 38105, USA
Camenzind G. Robinson
St. Jude Children’s Research Hospital, Cellular Imaging Shared Resource, Memphis, TN 38105, USA
Yvan Campos
St. Jude Children’s Research Hospital, Department of Genetics, Memphis, TN 38105, USA
Ashutosh Mishra
St. Jude Children’s Research Hospital, Center for Proteomics and Metabolomics, Memphis, TN 38105, USA
Leigh E. Fremuth
St. Jude Children’s Research Hospital, Department of Genetics, Memphis, TN 38105, USA
Elida Gomero
St. Jude Children’s Research Hospital, Department of Genetics, Memphis, TN 38105, USA
Huimin Hu
St. Jude Children’s Research Hospital, Department of Genetics, Memphis, TN 38105, USA
Alessandra d’Azzo
St. Jude Children’s Research Hospital, Department of Genetics, Memphis, TN 38105, USA; University of Tennessee Health Science Center, Department of Anatomy and Physiology, Memphis, TN 38163, USA; Corresponding author
Summary: 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.
