Rac1 selective activation improves retina ganglion cell survival and regeneration.
Rac1 selective activation improves retina ganglion cell survival and regeneration.
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DOI：
10.1371/journal.pone.0064350
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Buffelli M
中科院分区：
文献类型：
--
作者：
Lorenzetto E;Ettorre M;Pontelli V;Bolomini-Vittori M;Bolognin S;Zorzan S;Laudanna C;Buffelli M
在成年哺乳动物中，视神经损伤后，视网膜神经节细胞(RGC)不能再生其轴突，大多数在几天内死于细胞凋亡。最近，几种激活神经元细胞内通路的策略被提出以防止这种退化过程。Rho相关的小GTPase rac1是一个复杂的细胞内信号网络的一部分，目前还不完全清楚，它在神经元中调节许多作用，包括轴突生长和细胞生存。然而，它在体内神经元存活和再生中的作用还没有得到适当的研究。为了解决这一点，我们在视神经挤压后选择性地向玻璃体内注射了穿透性细胞的rac1突变体，并研究了其对RGC存活和轴突再生的影响。我们注射了两个特性良好的L61成分活性TAT-rac1融合蛋白突变体，其中第二个F37A或Y40C突变使下游信号通路具有选择性。结果表明，在挤压后15天，两个突变体都能提高存活率并防止树突退化，而携带F37A突变的突变体也能促进轴突再生。用F37A突变体处理1个月后，轴突延长至15天时未见改善。此外，我们还发现F37A处理后视网膜神经节细胞中Ak1T212的磷酸化和ERK1/2的表达增加，而Y40C处理后的胶质细胞中ERK1/2的活化程度更高。我们的数据表明，选择性激活不同的rac1依赖通路可能代表着一种对抗视网膜神经元退化过程的治疗策略。
In adult mammals, after optic nerve injury, retinal ganglion cells (RGCs) do not regenerate their axons and most of them die by apoptosis within a few days. Recently, several strategies that activate neuronal intracellular pathways were proposed to prevent such degenerative processes. The rho-related small GTPase Rac1 is part of a complex, still not fully understood, intracellular signaling network, mediating in neurons many effects, including axon growth and cell survival. However, its role in neuronal survival and regeneration in vivo has not yet been properly investigated. To address this point we intravitreally injected selective cell-penetrating Rac1 mutants after optic nerve crush and studied the effect on RGC survival and axonal regeneration. We injected two well-characterized L61 constitutively active Tat-Rac1 fusion protein mutants, in which a second F37A or Y40C mutation confers selectivity in downstream signaling pathways. Results showed that, 15 days after crush, both mutants were able to improve survival and to prevent dendrite degeneration, while the one harboring the F37A mutation also improved axonal regeneration. The treatment with F37A mutant for one month did not improve the axonal elongation respect to 15 days. Furthermore, we found an increase of Pak1 T212 phosphorylation and ERK1/2 expression in RGCs after F37A treatment, whereas ERK1/2 was more activated in glial cells after Y40C administration. Our data suggest that the selective activation of distinct Rac1-dependent pathways could represent a therapeutic strategy to counteract neuronal degenerative processes in the retina.
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影响因子：
3.8
作者：
Fujimura, Masatake;Usuki, Fusako;Izumo, Shuji
通讯作者：
Izumo, Shuji
DOI：
10.1073/pnas.1119449109
发表时间：
2012-06-05
影响因子：
11.1
作者：
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作者：
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通讯作者：
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影响因子：
64.5
作者：
Lamarche, N;Tapon, N;Hall, A
通讯作者：
Hall, A