Everett C M, Wood N W
Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, UK.
Brain. 2004 Nov;127(Pt 11):2385-405. doi: 10.1093/brain/awh278. Epub 2004 Aug 25.
Major insights have been attained into the molecular pathology of the trinucleotide repeat neurodegenerative diseases over the past decade. Genetic definition has allowed subclassification into translated polyglutamine diseases, which are due to CAG repeat expansions, and a more heterogeneous group in which the trinucleotide repeat remains untranslated. The polyglutamine disorders are due to a toxic gain of function of mutant expanded proteins. Neuronal intranuclear inclusions (NIIs) characteristically occur. Protein misfolding, interference with DNA transcription and RNA processing, activation of apoptosis and dysfunction of cytoplasmic elements have all been invoked in the toxic process. The end result is apoptotic cell death with many aspects of neuronal function being perturbed. Promising progress has been made into arresting and reversing neurodegeneration in both cellular and animal models. The molecular mechanisms underlying the untranslated group remain less clear. Impedance of gene transcription secondary to abnormal DNA structures formed by repeats, modification of chromatin gene packaging and dysfunction at the RNA level have all been suggested as possible pathological mechanisms. These diseases remain irreversible. It is hoped that clarification of the molecular pathogenic mechanisms will provide the tools for future therapeutic intervention.
在过去十年中，我们对三核苷酸重复神经退行性疾病的分子病理学有了重大认识。基因定义已允许将其细分为由CAG重复扩增引起的翻译型多聚谷氨酰胺疾病，以及三核苷酸重复未翻译的更异质的一组疾病。多聚谷氨酰胺疾病是由于突变扩展蛋白的毒性功能获得。特征性地出现神经元核内包涵体（NIIs）。蛋白质错误折叠、对DNA转录和RNA加工的干扰、细胞凋亡的激活以及细胞质元件的功能障碍都在毒性过程中被提及。最终结果是凋亡性细胞死亡，神经元功能的许多方面受到干扰。在细胞和动物模型中，在阻止和逆转神经退行性变方面已经取得了有希望的进展。未翻译组疾病的潜在分子机制仍不太清楚。由重复形成的异常DNA结构继发的基因转录阻抗、染色质基因包装的修饰以及RNA水平的功能障碍都被认为是可能的病理机制。这些疾病仍然是不可逆的。希望对分子致病机制的阐明将为未来的治疗干预提供工具。
