Department of Biological Sciences, Vanderbilt University and Medical Center, Nashville, TN 37235, USA.
Department of Cell and Developmental Biology, Vanderbilt University and Medical Center, Nashville, TN 37235, USA.
Dis Model Mech. 2023 Oct 1;16(10). doi: 10.1242/dmm.050206. Epub 2023 Oct 12.
The lipid storage disease Niemann Pick type C (NPC) causes neurodegeneration owing primarily to loss of NPC1. Here, we employed a Drosophila model to test links between glycosphingolipids, neurotransmission and neurodegeneration. We found that Npc1a nulls had elevated neurotransmission at the glutamatergic neuromuscular junction (NMJ), which was phenocopied in brainiac (brn) mutants, impairing mannosyl glucosylceramide (MacCer) glycosylation. Npc1a; brn double mutants had the same elevated synaptic transmission, suggesting that Npc1a and brn function within the same pathway. Glucosylceramide (GlcCer) synthase inhibition with miglustat prevented elevated neurotransmission in Npc1a and brn mutants, further suggesting epistasis. Synaptic MacCer did not accumulate in the NPC model, but GlcCer levels were increased, suggesting that GlcCer is responsible for the elevated synaptic transmission. Null Npc1a mutants had heightened neurodegeneration, but no significant motor neuron or glial cell death, indicating that dying cells are interneurons and that elevated neurotransmission precedes neurodegeneration. Glycosphingolipid synthesis mutants also had greatly heightened neurodegeneration, with similar neurodegeneration in Npc1a; brn double mutants, again suggesting that Npc1a and brn function in the same pathway. These findings indicate causal links between glycosphingolipid-dependent neurotransmission and neurodegeneration in this NPC disease model.
神经鞘脂贮积病尼曼-皮克 C 型（NPC）主要由于 NPC1 的缺失而导致神经退行性变。在这里，我们利用果蝇模型来测试神经递质、神经传递和神经退行性变之间的联系。我们发现，Npc1a 缺失导致谷氨酸能神经肌肉接头（NMJ）处的神经传递升高，这在 brainiac（brn）突变体中得到了复制，损害了甘露糖基葡萄糖脑苷脂（MacCer）的糖基化。Npc1a；brn 双突变体具有相同的升高的突触传递，表明 Npc1a 和 brn 功能在同一途径内。用米格列醇抑制葡萄糖脑苷脂（GlcCer）合酶可防止 Npc1a 和 brn 突变体中升高的神经传递，进一步表明了上位性。在 NPC 模型中，突触 MacCer 没有积累，但 GlcCer 水平增加，表明 GlcCer 是升高的突触传递的原因。Npc1a 缺失突变体的神经退行性变加剧，但没有明显的运动神经元或神经胶质细胞死亡，表明死亡的细胞是中间神经元，并且升高的神经传递先于神经退行性变。糖脂合成突变体也有明显加剧的神经退行性变，Npc1a；brn 双突变体的神经退行性变也类似，这再次表明 Npc1a 和 brn 功能在同一途径内。这些发现表明在这个 NPC 疾病模型中，糖鞘脂依赖性神经传递和神经退行性变之间存在因果关系。
