Sari Youssef
Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, USA.
Int J Biomed Sci. 2011 Jun;7(2):89-100.
Huntington's disease (HD) is an inherited disorder characterized by neuronal dysfunction and degeneration in striatum and cerebral cortex. Although the signaling pathways involved in HD are not yet clearly elucidated, mutant huntingtin protein is a key factor in the induction of neurodegeneration. The mutant huntingtin protein alters intracellular Ca(2+) homeostasis, disrupts intracellular trafficking and impairs gene transcription. In this review, I emphasize the effects of mutant huntingtin protein in Ca(2+) handling and transcriptional factors. Transcriptional alterations are key factors in the deficits of several proteins involved in the cellular machinery. These proteins include neurotrophic factors such as brain-derived neurotrophic factor, fibroblast growth factor, glial-cell-line-derived neurotrophic factor, ciliary neurotrophic factor and neurturin that have been suggested to restore neuronal dysfunction, improve behavioral deficits and prolong the survival in animal models of HD. An understanding of the molecular pathways involved in neurodegeneration will shed light on the choice of neurotrophic factors targeting a specific neuronal population in HD and will consequently overcome behavioral deficits.
亨廷顿舞蹈症（HD）是一种遗传性疾病，其特征是纹状体和大脑皮质中的神经元功能障碍和退化。尽管尚未明确阐明HD所涉及的信号通路，但突变型亨廷顿蛋白是诱导神经退行性变的关键因素。突变型亨廷顿蛋白会改变细胞内Ca(2+)稳态，破坏细胞内运输并损害基因转录。在本综述中，我着重阐述突变型亨廷顿蛋白在Ca(2+)处理和转录因子方面的作用。转录改变是细胞机制中几种蛋白质缺陷的关键因素。这些蛋白质包括神经营养因子，如脑源性神经营养因子、成纤维细胞生长因子、胶质细胞系源性神经营养因子、睫状神经营养因子和神经营养素，它们已被建议用于恢复HD动物模型中的神经元功能障碍、改善行为缺陷并延长生存期。对神经退行性变所涉及分子途径的理解将有助于在HD中选择针对特定神经元群体的神经营养因子，从而克服行为缺陷。
