Regulation of Neuronal Cell Death and Neurodegeneration by Members of the Bcl-2 Family: Therapeutic Implications
Regulation of Neuronal Cell Death and Neurodegeneration by Members of the Bcl-2 Family: Therapeutic Implications
复制标题
DOI：
10.2174/1568007053005127
复制
发表时间：
2005-01-01
影响因子：
3
通讯作者：
Roth, Kevin A.
中科院分区：
文献类型：
--
作者：
Shacka, John J.;Roth, Kevin A.
Bcl-2蛋白家族包含抗凋亡和促凋亡成员，其已显示在发育期间以及在许多急性和慢性神经变性模型中调节神经元细胞死亡。该蛋白质家族可根据结构和功能分为三个不同的类别：抗凋亡亚组;促凋亡多结构域亚组;和促凋亡仅BH 3结构域亚组。Bcl-2家族成员表达的改变发生在几种动物和人类神经变性疾病中，包括阿尔茨海默病、亨廷顿病和帕金森病以及肌萎缩性侧索硬化症。在急性神经变性的体内和体外模型中也观察到类似的变化，包括中风和创伤性脑损伤。增加抗凋亡Bcl-2家族成员的总体表达和/或功能，从而促进神经元存活的方法已经在这些模型中被广泛研究。大多数治疗努力集中在通过病毒载体将Bcl-2家族成员的抗凋亡成员靶向递送到感兴趣的受影响的脑区域，产生小分子抑制剂与Bcl-2家族成员的直接相互作用，或继发于药理学操作的Bcl-2家族成员的诱导表达。尽管在设计用于治疗神经变性的安全有效的Bcl-2家族模拟物方面存在许多挑战，但这些策略为在各种人类神经系统疾病中保留神经元活力和功能提供了很大的希望。
The Bcl-2 family of proteins contains both anti and pro-apoptotic members that have been shown to regulate neuronal cell death during development and in many models of acute and chronic neurodegeneration. This family of proteins can be divided into three distinct classes based on structure and function: the antiapoptotic sub-group; the pro-apoptotic, multi-domain sub-group; and the pro-apoptotic, BH3 domain-only sub-group. Alterations in the expression of Bcl-2 family members occur in several animal and human neurodegenerative diseases including Alzheimer's, Huntington's and Parkinson's diseases and Amyotrophic Lateral Sclerosis. Similar changes are seen in in vivo and in vitro models of acute neurodegeneration, including stroke and traumatic brain injury. Methods to increase the overall expression and/or function of anti-apoptotic Bcl-2 family members, and thus promote neuron survival, have been studied extensively in these models. Most treatment efforts focus on either the targeted delivery via viral vectors of anti-apoptotic members of Bcl-2 family members into the affected brain regions of interest, the generation of direct interactions of small molecule inhibitors with Bcl-2 family members, or the induced expression of Bcl-2 family members secondary to pharmacological manipulation. Although many challenges exist in the design of safe and efficacious Bcl-2 family mimetics for the treatment of neurodegeneration, such strategies offer great promise for preserving neuron viability, and hopefully function, in a variety of human neurological diseases.