Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Human Biochemical Genetics Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Mol Genet Metab. 2021 Dec;134(4):330-336. doi: 10.1016/j.ymgme.2021.11.008. Epub 2021 Nov 16.
Niemann-Pick disease, type C1 is a progressive, lethal, neurodegenerative disorder due to endolysosomal storage of unesterified cholesterol. Cerebellar ataxia, as a result of progressive loss of cerebellar Purkinje neurons, is a major symptom of Nieman-Pick disease, type C1. Comparing single cell RNAseq data from control (Npc1) and mutant (Npc1) mice, we observed significantly decreased expression of Slc1a3 in Npc1 astrocytes. Slc1a3 encodes a glutamate transporter (GLAST, EAAT1) which functions to decrease glutamate concentrations in the post synaptic space after neuronal firing. Glutamate is an excitatory neurotransmitter and elevated extracellular levels of glutamate can be neurotoxic. Impaired EAAT1 function underlies type-6 episodic ataxia, a rare disorder with progressive cerebellar dysfunction, thus suggesting that impaired glutamate uptake in Niemann-Pick disease, type C1 could contribute to disease progression. We now show that decreased expression of Slc1a3 in Npc1 mice has functional consequences that include decreased surface protein expression and decreased glutamate uptake by Npc1 astrocytes. To test whether glutamate neurotoxicity plays a role in Niemann-Pick disease, type C1 progression, we treated NPC1 deficient mice with ceftriaxone and riluzole. Ceftriaxone is a β-lactam antibiotic that is known to upregulate the expression of Slc1a2, an alternative glial glutamate transporter. Although ceftriaxone increased Slc1a2 expression, we did not observe a treatment effect in NPC1 mutant mice. Riluzole is a glutamate receptor antagonist that inhibits postsynaptic glutamate receptor signaling and reduces the release of glutamate. We found that treatment with riluzole increased median survival in Npc1 by 12%. Given that riluzole is an approved drug for the treatment of amyotrophic lateral sclerosis, repurposing of this drug may provide a novel therapeutic approach to decrease disease progression in Niemann-Pick disease type, C1 patients.
尼曼-匹克病 C1 型是一种进行性、致命的神经退行性疾病，其病因是未酯化胆固醇在内溶酶体中的贮积。小脑共济失调是尼曼-匹克病 C1 型的主要症状之一，其原因是小脑浦肯野神经元进行性丧失。通过比较对照（Npc1）和突变（Npc1）小鼠的单细胞 RNAseq 数据，我们观察到 Npc1 星形胶质细胞中 Slc1a3 的表达显著降低。Slc1a3 编码谷氨酸转运体（GLAST、EAAT1），其功能是在神经元放电后降低突触后空间中的谷氨酸浓度。谷氨酸是一种兴奋性神经递质，细胞外谷氨酸水平升高可能具有神经毒性。EAAT1 功能障碍是 6 型发作性共济失调的基础，这是一种罕见的进行性小脑功能障碍疾病，因此提示尼曼-匹克病 C1 型中谷氨酸摄取的受损可能导致疾病进展。我们现在表明，Npc1 小鼠中 Slc1a3 的表达降低具有功能后果，包括表面蛋白表达降低和 Npc1 星形胶质细胞中谷氨酸摄取减少。为了测试谷氨酸神经毒性是否在尼曼-匹克病 C1 型进展中起作用，我们用头孢曲松和利鲁唑治疗 NPC1 缺陷小鼠。头孢曲松是一种β-内酰胺抗生素，已知可上调替代的神经胶质谷氨酸转运体 Slc1a2 的表达。尽管头孢曲松增加了 Slc1a2 的表达，但我们在 NPC1 突变小鼠中未观察到治疗效果。利鲁唑是一种谷氨酸受体拮抗剂，可抑制突触后谷氨酸受体信号传导并减少谷氨酸的释放。我们发现，利鲁唑治疗可使 Npc1 的中位生存期延长 12%。鉴于利鲁唑是治疗肌萎缩侧索硬化症的一种已批准药物，该药的重新利用可能为减少尼曼-匹克病 C1 型患者的疾病进展提供一种新的治疗方法。
