A role for thrombospondin-1 deficits in astrocyte-mediated spine and synaptic pathology in Down's syndrome.
A role for thrombospondin-1 deficits in astrocyte-mediated spine and synaptic pathology in Down's syndrome.
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DOI：
10.1371/journal.pone.0014200
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发表时间：
2010-12-02
期刊：
影响因子：
3.7
通讯作者：
Busciglio J
中科院分区：
文献类型：
--
作者：
Garcia O;Torres M;Helguera P;Coskun P;Busciglio J
唐氏综合征（DS）是最常见的智力低下的遗传原因。树突棘数量减少和结构异常是DS神经病理学的共同特征。然而，参与DS脊柱改变的机制尚不清楚。除了在突触形成和维持中的相关作用外，星形胶质细胞还可以通过释放可溶性因子或通过与神经元的物理接触来调节脊柱动力学。我们以前已经表明，受损的线粒体功能在DS星形胶质细胞导致蛋白质加工和分泌的代谢改变。在这项研究中，我们调查了星形胶质细胞功能的缺陷是否有助于DS脊柱病理学。使用人星形胶质细胞/大鼠海马神经元共培养，我们发现，DS星形胶质细胞直接参与脊柱畸形和突触密度降低的发展。我们还表明，血小板反应蛋白1（TSP-1），星形胶质细胞分泌的蛋白质，具有强大的调节作用，脊柱的数量和形态，DS的大脑和DS星形胶质细胞表现出显着的赤字TSP-1蛋白表达。正常星形胶质细胞中TSP-1的缺失导致脊柱形态的显著变化，而TSP-1水平的恢复阻止了DS星形胶质细胞介导的脊柱和突触改变。来自TSP-1 KO小鼠的星形胶质细胞培养物表现出与DS星形胶质细胞相似的支持棘形成和结构的缺陷。这些结果表明，人星形胶质细胞促进脊柱和突触形成，确定星形胶质细胞功能障碍作为DS脑中脊柱和突触病理学的重要因素，并为探索基于TSP-1的疗法治疗DS和其他神经系统疾病中的脊柱和突触病理学提供了机制原理。
Down's syndrome (DS) is the most common genetic cause of mental retardation. Reduced number and aberrant architecture of dendritic spines are common features of DS neuropathology. However, the mechanisms involved in DS spine alterations are not known. In addition to a relevant role in synapse formation and maintenance, astrocytes can regulate spine dynamics by releasing soluble factors or by physical contact with neurons. We have previously shown impaired mitochondrial function in DS astrocytes leading to metabolic alterations in protein processing and secretion. In this study, we investigated whether deficits in astrocyte function contribute to DS spine pathology. Using a human astrocyte/rat hippocampal neuron coculture, we found that DS astrocytes are directly involved in the development of spine malformations and reduced synaptic density. We also show that thrombospondin 1 (TSP-1), an astrocyte-secreted protein, possesses a potent modulatory effect on spine number and morphology, and that both DS brains and DS astrocytes exhibit marked deficits in TSP-1 protein expression. Depletion of TSP-1 from normal astrocytes resulted in dramatic changes in spine morphology, while restoration of TSP-1 levels prevented DS astrocyte-mediated spine and synaptic alterations. Astrocyte cultures derived from TSP-1 KO mice exhibited similar deficits to support spine formation and structure than DS astrocytes. These results indicate that human astrocytes promote spine and synapse formation, identify astrocyte dysfunction as a significant factor of spine and synaptic pathology in the DS brain, and provide a mechanistic rationale for the exploration of TSP-1-based therapies to treat spine and synaptic pathology in DS and other neurological conditions.
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影响因子：
2.5
作者：
Belichenko, PV;Masliah, E;Mobley, WC
通讯作者：
Mobley, WC
DOI：
10.1083/jcb.138.3.707
发表时间：
1997-08-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
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Bouck NP
影响因子：
25
作者：
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影响因子：
4.8
作者：
Deshpande, Atul;Win, Khin May;Busciglio, Jorge
通讯作者：
Busciglio, Jorge
影响因子：
56.9
作者：
Beattie, EC;Stellwagen, D;Malenka, RC
通讯作者：
Malenka, RC