Molecular insights into mechanisms of the cell death program: Role in the progression of neurodegenerative disorders
Molecular insights into mechanisms of the cell death program: Role in the progression of neurodegenerative disorders
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DOI：
10.2174/156720506778249461
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发表时间：
2006-09-01
影响因子：
2.1
通讯作者：
Landshamer, Stefan
中科院分区：
文献类型：
--
作者：
Culmsee, Carsten;Landshamer, Stefan
阿尔茨海默病(AD)边缘和皮质神经元突触变性和死亡是阿尔茨海默病(AD)认知功能障碍和行为异常表现的基本过程。尽管各种遗传和环境因素以及衰老过程本身可能导致AD的表现，但在实验模型和AD脑组织中的研究表明，潜在的神经退行性变与细胞凋亡的形态和生化特征有关。在细胞水平上，氧化应激及相关的DNA损伤、细胞内钙稳态的破坏或内质网应激可启动AD的神经细胞凋亡。细胞凋亡生化级联反应的分子机制已开始被认识，包括上游效应分子如PAR-4、P53和促凋亡的Bcl2家族成员，它们介导线粒体功能障碍和随后的促凋亡蛋白的释放，如细胞色素c或凋亡诱导因子(AIF)，以及随后的caspase依赖和非依赖的通路，最终导致蛋白质和核DNA的降解。细胞凋亡级联反应的调控是复杂的，涉及转录调控和转录后蛋白质修饰，如蛋白酶介导的裂解、泛素化或多聚ADP核糖化。最近，通过蛋白激酶和磷酸酶来调节蛋白质的磷酸化正在成为控制细胞死亡程序的前提机制。更好地了解神经细胞凋亡的分子基础将导致新的预防和治疗方法，以预防和治疗阿尔茨海默病和其他神经疾病的神经退变过程，其中程序性细胞死亡是突出的。
Synaptic degeneration and death of neurons in limbic and cortical brain regions are the fundamental processes responsible for the manifestation of cognitive dysfunction and behavioural abnormalities in Alzheimer's disease (AD). Despite the various genetic and environmental factors, and the aging process itself that may lead to the manifestation of AD, multiple evidence from studies in experimental models and in AD brain tissue demonstrate that the underlying neurodegeneration is associated with morphological and biochemical features of apoptosis. At the cellular level, neuronal apoptosis in AD may be initiated by oxidative stress and related DNA damage, disruption of cellular calcium homeostasis, or endoplasmic reticulum (ER) stress. The molecular mechanisms of the biochemical cascades of apoptosis are beginning to be understood and involve upstream effectors such as Par-4, p53, and pro-apoptotic Bcl-2 family members, which mediate mitochondrial dysfunction and subsequent release of pro-apoptotic proteins, such as cytochrome c or apoptosis inducing factor (AIF), and subsequent caspase-dependent and -independent pathways which finally result in degradation of proteins and nuclear DNA. The regulation of apoptotic cascades is complex and involves transcriptional control as well as posttranscriptional protein modifications, such as protease-mediated cleavage, ubiquitination or poly(ADP-ribosylation). More recently, the regulation of protein phosphorylation by kinases and phosphatases is emerging as a prerequisite mechanism in the control of the apoptotic cell death program. A better understanding of the molecular underpinnings of neuronal apoptosis will lead to novel preventive and therapeutic approaches to the neurodegenerative processes in Alzheimer's disease and other neurological disorders where programmed cell death is prominent.