PDF(Pubmed)
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.
摘要：
内质网-质膜(ER-PM)连接介导穿过神经元膜的Ca2+通量。这些膜接触位点的性质由它们的脂质含量定义，但很少有人关注鞘糖脂（GSL）。这里,我们发现GM1-神经节苷脂，神经元膜中丰富的GSL，是ER-PM连接的组成部分;它与突触蛋白/受体相互作用并调节Ca2信号传导。在神经退行性溶酶体贮积病模型中，GM1-神经节苷脂增多症,由于β-半乳糖苷酶缺乏，GM1在ER-PM连接处的致病性积累极大地改变了神经元Ca2稳态。机械上,我们显示GM1与磷酸化的N-甲基D-天冬氨酸受体（NMDAR）Ca2通道相互作用，从而增加Ca2+通量，激活细胞外信号调节激酶（ERK）信号，并在不增加突触连通性的情况下增加突触棘的数量。因此，GM1在ER-PM连接处的聚集会改变突触可塑性，并使GM1神经节苷异位症的广义神经元细胞死亡特征恶化。
