Synaptic dysfunction in disease and following injury in the developing and adult nervous system: Caveats in the choice of therapeutic intervention
Synaptic dysfunction in disease and following injury in the developing and adult nervous system: Caveats in the choice of therapeutic intervention
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DOI：
10.1016/j.neubiorev.2007.04.015
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发表时间：
2007-01-01
影响因子：
8.2
通讯作者：
Oppenheim, Ronald W.
中科院分区：
文献类型：
--
作者：
Gould, Thomas W.;Oppenheim, Ronald W.
大多数发育性和成年性神经退行性疾病的一个主要特征是特定神经元群的死亡。在很大程度上，由于在阐明发育过程中发生的神经元死亡的细胞和分子机制方面取得了进展，改善这些机制的方法通常集中在神经元死亡途径的操纵上。然而，最近来自各种神经病理动物模型研究的证据表明，轴突和突触的损伤早在死亡通路激活之前就已经存在。我们最近将这些发现扩展到最常见的家族性肌萎缩性侧索硬化症（fALS）动物模型。在fALS转基因小鼠中，通过缺失促凋亡基因Bax抑制细胞死亡途径可以完全挽救脊髓MNs，但不能预防疾病。然而，我们在神经肌肉连接处（NMJ）的脊髓MNs突触前末端以及深度去神经支配中观察到明显的异常。这些结果表明，旨在保留突触而不是体细胞的治疗方法可能更有效地治疗这些神经病变。(c) 2007 Elsevier Ltd.版权所有。
A cardinal feature of most developmental and adult onset neurodegenerative diseases is the death of specific populations of neurons. Largely as a result of the progress made in elucidating the cellular and molecular mechanisms underlying the neuronal death that occurs during development, approaches ameliorating them often focus on the manipulation of neuronal death pathways. Recent evidence derived from the Study of animal models of various neuropathological conditions, however, has revealed that damage to axons and synapses long precedes the activation of death pathways. We recently extended these findings to the most commonly studied animal model of familial amyotrophic lateral sclerosis (fALS). Inhibiting the cell death pathway by deletion of the pro-apoptotic gene Bax completely rescued spinal MNs yet failed to prevent disease in fALS transgenic mice. However, we observed distinct abnormalities within presynaptic terminals of spinal MNs at the neuromuscular junction (NMJ), as well as profound denervation. These results suggest that therapies aimed at preserving the synapse rather than the soma may be more effective at treating these neuropathologies. (c) 2007 Elsevier Ltd. All rights reserved.