Pathogenesis of nigral cell death in Parkinson's disease.
Pathogenesis of nigral cell death in Parkinson's disease.
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DOI：
10.1016/j.parkreldis.2004.10.012
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发表时间：
2005-06
影响因子：
4.1
通讯作者：
S. Przedborski
中科院分区：
文献类型：
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作者：
S. Przedborski
帕金森病（PD）主要是一种散发性疾病，其主要由黑质中多巴胺能神经元的死亡引起。其病因仍然是谜，而其发病机制开始被理解为一个多因素级联的有害因素。到目前为止，大多数对PD发病机制的见解来自PD的毒性模型，并表明多巴胺能神经元中产生的早期细胞扰动包括氧化应激和能量危机。这些改变，而不是杀死神经元，触发随后的死亡相关的分子途径，包括细胞凋亡的元素。PD中多巴胺能神经元的命运也可能受到其他因素的影响，如兴奋性毒性，从丘脑底核到黑质的多巴胺能输入增加，以及纹状体和黑质中出现的神经胶质反应。在极少数情况下，PD可能是家族性的，这些遗传形式也为黑质纹状体多巴胺能神经元死亡的发病机制提供了线索，包括蛋白质折叠和降解机制以及线粒体功能的异常。尽管有关PD的致病性级联反应仍有待进一步阐明，但所有上述改变的汇编开始揭示黑质多巴胺能神经元为何以及如何在这种突出疾病（即PD）中退化。
Parkinson's disease (PD) is primarily a sporadic condition which results mainly from the death of dopaminergic neurons in the substantia nigra. Its etiology remains enigmatic while its pathogenesis begins to be understood as a multifactorial cascade of deleterious factors. As of yet, most insights into PD pathogenesis are derived from toxic models of PD and show that the earlier cellular perturbations arising in dopaminergic neurons include oxidative stress and energy crisis. These alterations, rather than killing neurons, trigger subsequent death-related molecular pathways including elements of apoptosis. The fate of dopaminergic neurons in PD may also be influenced by additional factors such as excitotoxicity, emanating from the increased glutamatergic input from the subthalamic nucleus to the substantia nigra, and the glial response that arises in the striatum and the substantia nigra. In rare instances, PD can be familial, and those genetic forms have also provided clues to the pathogenesis of nigrostriatal dopaminergic neuron death including abnormalities in the mechanisms of protein folding and degradation as well as mitochondrial function. Although more remains to be elucidated about the pathogenic cascade in PD, the compilation of all of the aforementioned alterations starts to shed light on why and how nigral dopaminergic neurons may degenerate in this prominent disease, that is PD.