Exploring the contribution of astrocytes to Huntington disease

 描述（由申请人提供）：亨廷顿病（HD）是一种成人发病的常染色体显性神经退行性疾病，临床特征为认知、精神和运动缺陷，可发展为严重残疾和死亡。到目前为止，还没有有效的治疗HD。突变的亨廷顿蛋白（mHTT）广泛表达于神经元和非神经元细胞中，但神经变性严重影响脑中神经元细胞类型的少数子集。了解mhtt在非神经元细胞类型中产生的毒性以及这种选择性神经变性的基础可能对设计有效的治疗方法至关重要。 该提案的目标是扩大我们对全长mHTT（fl-mHTT）表达星形胶质细胞对HD神经变性的贡献的了解。星形胶质细胞对神经系统的正常功能和发育至关重要。它们参与调节突触活动和神经传递。来自我们实验室的研究已经揭示了在取自条件性fl-mHTT表达BACHD小鼠模型的培养物中星形胶质细胞的SNARE依赖性谷氨酸释放增加。这是新发现的由星形胶质细胞中fl-mHTT表达引起的破坏，这进一步表明这些细胞与HD发病机制有关。此外，我们证明，减少fl-mHTT在体内星形胶质细胞中的表达，有助于在条件性BACHD小鼠模型中观察到的行为和神经病理表型。这里提出的研究将进一步了解星形胶质细胞对HD的贡献，并确定是否值得针对这种细胞类型进行治疗干预。我们将在这些研究中使用条件遗传小鼠模型，并提出三个目的：1）确定表达fl-mHTT的星形胶质细胞是否通过谷氨酸的胞吐作用增加BACHD小鼠中的谷氨酸水平而有助于HD发病机制; 2）确定星形胶质细胞中突变亨廷顿蛋白的表达是否有助于在BACHD小鼠中观察到的异常中等多刺神经元生理学;和3）确定BACHD小鼠疾病发作后星形胶质细胞中fl-mHTT表达的降低是否足以减轻HD症状，以及新小鼠模型中星形胶质细胞特异性表达是否足以在小鼠中引起HD样表型。这些研究将有助于确定星形胶质细胞内fl-mHTT在HD发病机制中的作用，并可能导致HD治疗的新治疗方法。

 DESCRIPTION (provided by applicant): Huntington's disease (HD) is an adult-onset autosomal dominant neurodegenerative disorder characterized clinically by cognitive, psychiatric and motor deficits which progress to severe disability and death. To date there are no affective treatments for HD. The mutated huntingtin (mHTT) protein is widely expressed in neuronal and non-neuronal cells, yet neurodegeneration critically affects a few subsets of neuronal cell types in the brain. Understanding the toxicity produced by mhtt in non-neuronal cell types and the basis for this selective neurodegeneration are likely to be critical in the desin of effective therapies for the disease. The goal of this proposal is to expand our knowledge of the contribution of full length-mHTT (fl-mHTT) expressing astrocytes to neurodegeneration in HD. Astrocytes are critical to the proper function and development of the nervous system. They are involved in modulating synaptic activity and neurotransmission. Studies from our laboratory have uncovered increased SNARE-dependent glutamate release from astrocytes in culture taken from the conditional fl-mHTT expressing BACHD mouse model. This is a new found disruption caused by fl-mHTT expression in the astrocytes, which further implicates these cells in HD pathogenesis. Furthermore, we demonstrate that reducing fl-mHTT expression in astrocytes in vivo, contributes to the behavioral and neuropathological phenotypes observed in the conditional BACHD mouse model. The studies proposed here will further our understanding of astrocyte contribution to HD and determine if targeting this cell type for therapeutic intervention is worthwhile. We will use conditional genetic mouse models in these studies and propose three aims: 1) To determine if fl-mHTT expressing astrocytes contribute to HD pathogenesis by increasing glutamate levels in BACHD mice through exocytosis of glutamate; 2) To determine if expression of mutant huntingtin in astrocytes contributes to the abnormal medium spiny neuron physiology observed in BACHD mice; and 3) To determine if decreasing fl-mHTT expression in astrocytes after disease onset in BACHD mice is sufficient to alleviate HD symptoms and whether astrocyte specific expression in a new mouse model is sufficient to cause HD-like phenotypes in mice. Together these studies will help to define the role of fl-mHTT within astrocytes in HD pathogenesis, and may lead to novel therapeutic approaches for treatment of HD.