Adenosine A2A receptor stimulation restores cell functions and differentiation in Niemann-Pick type C-like oligodendrocytes
Adenosine A2A receptor stimulation restores cell functions and differentiation in Niemann-Pick type C-like oligodendrocytes
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DOI：
10.1038/s41598-019-46268-8
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发表时间：
2019-07-05
影响因子：
4.6
通讯作者：
Minghetti, Luisa
中科院分区：
文献类型：
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作者：
De Nuccio, Chiara;Bernardo, Antonietta;Minghetti, Luisa
Niemann Pick C型(NPC)病是一种罕见的神经内脏疾病。NPC1基因突变导致未酯化胆固醇在细胞内体/溶酶体系统内积聚，导致细胞死亡。我们最近发现，刺激腺苷A(2A)受体(A(2A)R)可以恢复NPC1 siRNA瞬时转染的人鼻咽癌成纤维细胞和神经细胞系中晚期内小体/溶酶体中胆固醇的积聚，这表明这些受体可能是对比疾病的靶点。由于NPC1病的特点是少突胶质前体细胞(OPs)髓鞘异常和成熟停滞，本研究探讨A(2A)R刺激能否促进少突胶质细胞分化和髓鞘形成，从而克服这些重要的神经系统异常。我们建立了一个NPC1药理模型，在该模型中，OPs的原代培养物暴露于胆固醇转运抑制剂，以诱导NPC1样表型，其特征包括：(I)胆固醇积聚，(Ii)线粒体改变！形态和膜电位，(Iii)自噬缺陷和(Iv)成熟停滞。A(2A)受体激动剂CGS21680使所有NPC1样特征正常化。CGS21680将OP从成熟停滞中解救出来，并促进其向成熟OL分化的能力，提示A(2A)R刺激可能被用来纠正NPC1的髓鞘障碍，进一步支持它们在疾病中的治疗潜力。
Niemann Pick type C (NPC) disease is a rare neurovisceral disorder. Mutations in npc1 gene induce an intracellular accumulation of unesterified cholesterol in the endosomal/lysosomal system causing cell death. We recently showed that stimulation of adenosine A(2A) receptors (A(2A)R) restores cholesterol accumulation in late endosomes/lysosomes in human NPC fibroblasts and neural cell lines transiently transfected with NPC1 siRNA, suggesting that these receptors might be targeted to contrast the disease. Since NPC1 disease is characterized by dysmyelination and maturational arrest of oligodendrocyte progenitors (OPs), in this study, we investigated whether A(2A)R stimulation could promote oligodendrocyte differentiation and myelin formation, thus overcoming these important neurological abnormalities. We developed a NPC1 pharmacological model, in which primary cultures of OPs are exposed to a cholesterol transport inhibitor to induce a NPC1-like phenotype characterized by several typical features such as (i) cholesterol accumulation, (ii) altered mitochondria! morphology and membrane potential, (iii) defect of autophagy and (iv) maturation arrest. The A(2A)R agonist CGS21680 normalized all NPC1-like features. The ability of CGS21680 of rescuing OP from maturational arrest and promoting their differentiation to mature OL, suggests that A(2A)R stimulation might be exploited to correct dysmyelination in NPC1, further supporting their therapeutic potential in the disease.