Susceptibility to neurodegeneration in a glaucoma is modified by Bax gene dosage.
Susceptibility to neurodegeneration in a glaucoma is modified by Bax gene dosage.
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DOI：
10.1371/journal.pgen.0010004
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发表时间：
2005-07
期刊：
影响因子：
4.5
通讯作者：
John SW
中科院分区：
文献类型：
--
作者：
Libby RT;Li Y;Savinova OV;Barter J;Smith RS;Nickells RW;John SW
在青光眼中，有害的眼内压通常导致视网膜神经节细胞死亡。然而，目前尚不清楚眼内压是否直接损害视网膜神经节细胞轴突、索马或两者。介导压力诱导的视网膜神经节细胞死亡的途径定义不清，并且已知不需要分子。DBA/2 J小鼠在促凋亡分子BCL 2相关的X蛋白（BAX）缺陷被用来研究BAX介导的细胞死亡途径在青光眼中的作用。Bax +/−和Bax −/−小鼠均未发生视网膜神经节细胞死亡。相反，轴突变性在Bax +/−或Bax −/−小鼠中均未得到预防。虽然BAX缺乏不能阻止轴突变性，但它确实减缓了轴突丢失。此外，我们比较了BAX缺乏对青光眼的影响，其对视网膜神经节细胞死亡的影响，由于两种损伤，提出参与青光眼。在青光眼中，BAX缺陷保护视神经挤压造成轴突损伤后的视网膜神经节细胞。然而，它不能保护视网膜神经节细胞免受N-甲基-D-天冬氨酸（NMDA）诱导的兴奋性毒性。BAX是遗传性青光眼中视网膜神经节细胞死亡所必需的;然而，它不是视网膜神经节细胞轴突变性所必需的。这表明，不同的体细胞和轴突变性途径是活跃的青光眼。最后，我们的数据支持视神经损伤的作用，但不是NMDA受体介导的兴奋性毒性在青光眼。这些发现表明需要了解青光眼中的轴突特异性变性途径，并且它们表明可能需要靶向不同的体细胞和轴突变性途径来挽救视力。青光眼是一组疾病，其统一特征是连接眼睛和大脑的神经细胞（视网膜神经节细胞）死亡。青光眼通常与眼内有害的高压（眼内压）相关，导致神经细胞死亡。各种治疗用于降低眼压，但目前没有常用的治疗方法直接保护神经细胞。DBA/2 J小鼠随着年龄的增长眼压升高，这种压力会杀死视网膜神经细胞。作者使用这种小鼠模型来研究这些神经细胞如何在青光眼中死亡。他们表明，在视网膜神经细胞的不同部分有不同的变性途径被激活。他们发现，位于视网膜中的神经细胞体中的生化途径需要一种称为BAX（BCL 2相关X蛋白）的分子。相比之下，连接细胞体和大脑的细胞部分（轴突）中的通路不需要BAX。由于细胞体和轴突的变性途径在人类青光眼中也可能在分子上不同，因此在设计治疗方法时将它们全部考虑在内是很重要的。他们的数据还表明BAX基因是调节青光眼易感性的候选基因。
In glaucoma, harmful intraocular pressure often contributes to retinal ganglion cell death. It is not clear, however, if intraocular pressure directly insults the retinal ganglion cell axon, the soma, or both. The pathways that mediate pressure-induced retinal ganglion cell death are poorly defined, and no molecules are known to be required. DBA/2J mice deficient in the proapoptotic molecule BCL2-associated X protein (BAX) were used to investigate the roles of BAX-mediated cell death pathways in glaucoma. Both Bax +/− and Bax −/− mice were protected from retinal ganglion cell death. In contrast, axonal degeneration was not prevented in either Bax +/− or Bax −/− mice. While BAX deficiency did not prevent axonal degeneration, it did slow axonal loss. Additionally, we compared the effects of BAX deficiency on the glaucoma to its effects on retinal ganglion cell death due to two insults that are proposed to participate in glaucoma. As in the glaucoma, BAX deficiency protected retinal ganglion cells after axon injury by optic nerve crush. However, it did not protect retinal ganglion cells from N-methyl-D-aspartate (NMDA)-induced excitotoxicity. BAX is required for retinal ganglion cell death in an inherited glaucoma; however, it is not required for retinal ganglion cell axon degeneration. This indicates that distinct somal and axonal degeneration pathways are active in this glaucoma. Finally, our data support a role for optic nerve injury but not for NMDA receptor-mediated excitotoxicity in this glaucoma. These findings indicate a need to understand axon-specific degeneration pathways in glaucoma, and they suggest that distinct somal and axonal degeneration pathways may need to be targeted to save vision. Glaucoma is a group of diseases whose unifying characteristic is death of nerve cells (retinal ganglion cells) that connect the eye to the brain. Glaucoma is often associated with a harmfully high pressure inside the eye (intraocular pressure) contributing to nerve cell death. Various treatments are used to lower eye pressure, but currently no commonly used treatments directly protect the nerve cells. DBA/2J mice develop elevated eye pressure with age, and this pressure kills retinal nerve cells. The authors use this mouse model to investigate how these nerve cells die in glaucoma. They show that there are distinct degeneration pathways activated in different parts of the retinal nerve cells. They found that the biochemical pathway in the nerve cell body, which resides in the retina, requires a molecule called BAX (BCL2-associated X protein). In contrast, pathways in the part of the cell (axon) that connects the cell body to the brain do not require BAX. Because degeneration pathways in the cell body and of the axon also may be molecularly different in human glaucoma, it will be important to consider them all when designing therapies. Their data also suggest that the BAX gene is a candidate to modulate glaucoma susceptibility.
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影响因子：
3.5
作者：
Kermer, P;Klöcker, N;Bähr, M
通讯作者：
Bähr, M
影响因子：
56.9
作者：
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30.8
作者：
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影响因子：
4.4
作者：
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通讯作者：
Weinreb, RN
影响因子：
3.4
作者：
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通讯作者：
SHARMA, SC