Buard Isabelle, Pfrieger Frank W
CNRS UPR 3212, University of Strasbourg, Institute of Cellular and Integrative Neurosciences (INCI), 67084 Strasbourg, France.
CNRS UPR 3212, University of Strasbourg, Institute of Cellular and Integrative Neurosciences (INCI), 67084 Strasbourg, France.
Mol Cell Neurosci. 2014 Jul;61:65-71. doi: 10.1016/j.mcn.2014.06.003. Epub 2014 Jun 7.
Niemann-Pick type C disease is a rare and ultimately fatal lysosomal storage disorder with variable neurologic symptoms. The disease-causing mutations concern NPC1 or NPC2, whose dysfunction entails accumulation of cholesterol in the endosomal-lysosomal system and the selective death of specific neurons, namely cerebellar Purkinje cells. Here, we investigated whether neurodegeneration is preceded by an imbalance of synaptic input to Purkinje cells and whether neuronal or glial absence of NPC1 has different impacts on synapses. To this end, we prepared primary cerebellar cultures from wildtype or NPC1-deficient mice that are glia-free and highly enriched with Purkinje cells. We report that lack of NPC1 in either neurons or glial cells did not affect the excitability of Purkinje cells, the formation of dendrites or their excitatory synaptic activity. However, simultaneous absence of NPC1 from neuronal and glial cells impaired the presynaptic input to Purkinje cells suggesting a cooperative effect of neuronal and glial NPC1 on synapses.
尼曼-皮克C型病是一种罕见且最终致命的溶酶体贮积症，伴有多种神经症状。致病突变涉及NPC1或NPC2，其功能障碍导致胆固醇在内体-溶酶体系统中蓄积，并导致特定神经元即小脑浦肯野细胞选择性死亡。在此，我们研究了浦肯野细胞突触输入失衡是否先于神经退行性变，以及神经元或神经胶质细胞中NPC1的缺失对突触是否有不同影响。为此，我们从野生型或NPC1缺陷型小鼠制备了原代小脑培养物，这些培养物不含神经胶质细胞且高度富集浦肯野细胞。我们报告，神经元或神经胶质细胞中NPC1的缺失均不影响浦肯野细胞的兴奋性、树突的形成或其兴奋性突触活动。然而，神经元和神经胶质细胞同时缺失NPC1会损害浦肯野细胞的突触前输入，提示神经元和神经胶质细胞中的NPC1对突触具有协同作用。
