Mutation of ataxia-telangiectasia mutated is associated with dysfunctional glutathione homeostasis in cerebellar astroglia.
Mutation of ataxia-telangiectasia mutated is associated with dysfunctional glutathione homeostasis in cerebellar astroglia.
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DOI：
10.1002/glia.22925
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发表时间：
2016-02
期刊：
影响因子：
6.2
通讯作者：
Mayer-Pröschel M
中科院分区：
文献类型：
--
作者：
Campbell A;Bushman J;Munger J;Noble M;Pröschel C;Mayer-Pröschel M
星形胶质细胞功能障碍在神经退行性疾病中起重要作用，否则归因于神经元功能丧失。在这里，我们专注于星形胶质细胞在共济失调-毛细血管扩张症（A-T）中的作用，这是一种由共济失调-毛细血管扩张症突变（ATM）基因突变引起的疾病。A-T病理学的一个标志是小脑神经元的进行性丧失，但影响神经元存活的机制尚不清楚。我们现在提供了一个可能的机制，A-T星形胶质细胞影响小脑神经元的存活。由于星形胶质细胞的功能很难在体内环境中研究，特别是在小脑中，这些细胞与数量多得多的神经元交织在一起，我们进行了体外共培养实验，允许纯化的细胞群的产生和药理学操作。我们的分析显示，从Atm突变小鼠分离的小脑星形胶质细胞显示胱氨酸/谷氨酸交换亚基xCT、谷胱甘肽（GSH）还原酶和谷胱甘肽-S-转移酶的表达降低。我们还发现A-T星形胶质细胞中细胞间和分泌型GSH水平降低。谷胱甘肽的主要前体L-胱氨酸的代谢标记显示，A-T星形胶质细胞缺陷的一个关键组成部分是输入谷胱甘肽生产的限速前体的能力受损。这种损伤导致细胞外GSH供应不佳，这反过来又损害了小脑神经元的存活。我们表明，通过添加N-乙酰基-L-半胱氨酸（NAC）作为替代半胱氨酸来源，绕过了L-胱氨酸的xCT依赖性输入，我们能够恢复A-T突变星形胶质细胞中的GSH水平，为靶向治疗干预提供了一种可能的未来途径。
Astroglial dysfunction plays an important role in neurodegenerative diseases otherwise attributed to neuronal loss of function. Here we focus on the role of astroglia in ataxia–telangiectasia (A–T), a disease caused by mutations in the ataxia–telangiectasia mutated (ATM) gene. A hallmark of A–T pathology is progressive loss of cerebellar neurons, but the mechanisms that impact neuronal survival are unclear. We now provide a possible mechanism by which A–T astroglia affect the survival of cerebellar neurons. As astroglial functions are difficult to study in an in vivo setting, particularly in the cerebellum where these cells are intertwined with the far more numerous neurons, we conducted in vitro coculture experiments that allow for the generation and pharmacological manipulation of purified cell populations. Our analyses revealed that cerebellar astroglia isolated from Atm mutant mice show decreased expression of the cystine/glutamate exchanger subunit xCT, glutathione (GSH) reductase, and glutathione-S-transferase. We also found decreased levels of intercellular and secreted GSH in A–T astroglia. Metabolic labeling of L-cystine, the major precursor for GSH, revealed that a key component of the defect in A–T astroglia is an impaired ability to import this rate-limiting precursor for the production of GSH. This impairment resulted in suboptimal extracellular GSH supply, which in turn impaired survival of cerebellar neurons. We show that by circumventing the xCT-dependent import of L-cystine through addition of N-acetyl-L-cysteine (NAC) as an alternative cysteine source, we were able to restore GSH levels in A–T mutant astroglia providing a possible future avenue for targeted therapeutic intervention.
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DOI：
10.1097/00005072-197911000-00007
发表时间：
1979-01-01
影响因子：
3.2
作者：
AMROMIN, GD;BODER, E;TEPLITZ, R
通讯作者：
TEPLITZ, R
DOI：
10.1073/pnas.0813361106
发表时间：
2009-02-24
影响因子：
11.1
作者：
Chen, Pei-Chun;Vargas, Marcelo R.;Johnson, Jeffrey A.
通讯作者：
Johnson, Jeffrey A.
影响因子：
3
作者：
Albrecht, Philipp;Lewerenz, Jan;Methner, Axel
通讯作者：
Methner, Axel
DOI：
10.1523/jneurosci.2323-09.2009
发表时间：
2009-08-26
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
David Y;Cacheaux LP;Ivens S;Lapilover E;Heinemann U;Kaufer D;Friedman A
通讯作者：
Friedman A
影响因子：
64.5
作者：
Barlow, C;Hirotsune, S;WynshawBoris, A
通讯作者：
WynshawBoris, A