Decreased estradiol release from astrocytes contributes to the neurodegeneration in a mouse model of Niemann-Pick disease type C
Decreased estradiol release from astrocytes contributes to the neurodegeneration in a mouse model of Niemann-Pick disease type C
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DOI：
10.1002/glia.20563
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发表时间：
2007-11-15
期刊：
影响因子：
6.2
通讯作者：
Duan, Shumin
中科院分区：
文献类型：
--
作者：
Chen, Gang;Li, Hai-Min;Duan, Shumin
C型尼曼-匹克病（NPC）是一种致命的神经退行性疾病，通常由称为NPC 1的基因突变引起，该基因突变导致未酯化胆固醇和鞘糖脂在内体-溶酶体系统中积聚。关于NPC神经退行性变机制的研究大多集中在神经元。然而，也存在NPC 1通过作用于与神经元密切相互作用的其他细胞而间接影响神经元功能的可能性。在这项研究中，使用异型神经元-胶质细胞共培养系统，我们发现，野生型神经元上培养的一层NPC 1-/-星形胶质细胞的神经突起生长减少相比，野生型星形胶质细胞上培养的。RT-PCR和免疫组化评估显示，NPC 1-/-星形胶质细胞培养物中神经类固醇酶和星星（类固醇生成急性调节蛋白）的表达显著低于野生型培养物。此外，从星形胶质细胞培养基和NPC 1-/-小鼠的全脑中测量到雌二醇水平降低。给新生的NPC 1-/-小鼠施用17 β-雌二醇显著延迟了神经系统症状的发作，增加了浦肯野细胞的存活，并延长了动物的寿命。我们的研究结果表明，星形胶质细胞功能障碍导致NPC的神经退行性变，雌二醇治疗可能有助于改善疾病的进展。(C)2007 Wiley-Liss，Inc.
Niemann-Pick disease type C (NPC) is a deadly neurodegenerative disease often caused by mutation in a gene called NPC1, which results in the accumulation of unesterified cholesterol and glycosphingolipids in the endosomal-lysosomal system. Most studies on the mechanisms of neurodegeneration in NPC have focused on neurons. However, the possibility also exists that NPC1 affects neuronal functions indirectly by acting on other cells that are intimately interacting with neurons. In this study, using a heterotypic neuron-glia coculture system, we found that wild-type neurons cultured on a layer of NPC1-/- astrocytes showed decreased neurite growth compared with those cultured on wild-type astrocytes. RT-PCR and immunohistochemical assessments showed significantly lower expression of neurosteroid enzymes and StAR (steroidogenic acute regulatory protein) in NPC1-/- astrocyte cultures than in wild-type cultures. Furthermore, a reduced level of estradiol was measured from both astrocyte culture medium and whole brains from NPC1-/- mice. Administration of 17 beta-estradiol to neonatal NPC1-/- mice significantly delayed the onset of neurological symptoms, increased Purkinje cell survival, and extended the animals' life span. Our findings suggest that astrocyte dysfunction contributes to the neurodegeneration of NPC and estradiol treatment may be useful in ameliorating progression of the disease. (C) 2007 Wiley-Liss, Inc.