Glial huntingtin and neurodegeneration

 描述（由申请人提供）：亨廷顿病（HD）是一种年龄依赖性神经退行性疾病家族，包括阿尔茨海默病（AD）和帕金森病（PD）。这些疾病的特征在于由错误折叠的蛋白质以年龄依赖性方式引起的选择性神经变性。在HD中，疾病蛋白亨廷顿蛋白（htt）携带扩展的多聚谷氨酰胺重复序列，在大脑中积累，随着患者变老而形成聚集体，并导致进行性神经系统症状。鉴于HD中已知的基因突变及其良好的神经病理学特征，HD是研究选择性神经病理学如何以年龄依赖性方式发生的理想模型。大多数先前的研究集中在突变htt对神经元细胞的影响，并揭示了突变htt的N-末端片段错误折叠，并在各种动物模型中引起细胞自主和非细胞自主的病理事件。在大脑中，大多数细胞是非神经元细胞，为神经元细胞的生存和功能提供必要的支持。这些非神经元细胞主要由三种类型的胶质细胞组成：星形胶质细胞、小胶质细胞和少突胶质细胞。已知少突胶质细胞产生用于轴突髓鞘形成的髓鞘蛋白，并且星形胶质细胞可以释放神经营养因子以支持神经元存活和功能。然而，胶质细胞中的突变htt是否影响这些重要功能仍有待研究。我们已经建立了转基因小鼠模型，表达突变htt特异性星形胶质细胞（GFAP-160 Q）或少突胶质细胞（PLP-150 Q）。这两种HD小鼠模型均发展出年龄依赖性神经表型，表明胶质细胞中的突变htt在衰老过程中影响胶质功能，并对年龄依赖性临床表型做出重要贡献。我们还发现，在我们的GFAP-160 Q HD转基因小鼠中，突变htt可以减少星形胶质细胞的BDNF释放，并引起脱髓鞘或神经元死亡，这让人想起先前HD小鼠模型和人类HD患者大脑中的病理事件。在本申请中，我们提出了三个目标来研究胶质细胞中突变htt的表达如何导致HD转基因小鼠的神经元功能障碍和神经表型。目的1研究突变htt对胶质细胞分泌神经营养因子的影响。目的二是探讨胶质细胞htt突变如何引起年龄依赖性神经表型和神经病理学改变。目的3探讨降低胶质细胞htt或改善胶质细胞功能对HD的保护作用 老鼠的大脑这些研究将有助于了解HD中年龄依赖性神经病理学的机制以及胶质细胞htt对HD病理学的贡献。由于神经胶质细胞是治疗的理想移植群体，因此我们的研究结果也可能为治疗HD提供新的治疗靶点。

 DESCRIPTION (provided by applicant): Huntington's disease (HD) represents an age-dependent neurodegenerative disease family including Alzheimer's (AD) and Parkinson's (PD) diseases. These diseases are characterized by selective neurodegeneration that is caused by misfolded proteins in an age-dependent manner. In HD, the disease protein huntingtin (htt) carries an expanded polyglutamine repeat, accumulates in the brain, forms aggregates as patients become old, and causes progressive neurological symptoms. Given the known genetic mutation in HD and its well-characterized neuropathology, HD makes an ideal model for investigating how selective neuropathology occurs in an age-dependent manner. Most previous studies focused on the effect of mutant htt on neuronal cells and revealed that N-terminal fragments of mutant htt are misfolded and cause cell-autonomous and non-cell-autonomous pathological events in a variety of animal models. In the brain, the majority of cells are non-neuronal cells that provide essential support to the survival and function of neuronal cells. These non-neuronal cells mainly consist of three types of glial cells: astrocytes, microglial cells and oligodendrocytes. It is known that oligodendrocytes produce myelin proteins for myelination of axons, and astrocytes can release neurotrophins to support neuronal survival and function. However, whether mutant htt in glial cells affects these important functions remains to be investigated. We have established transgenic mouse models that express mutant htt specifically in astrocytes (GFAP-160Q) or oligodendrocytes (PLP-150Q). Both HD mouse models develop age-dependent neurological phenotypes, suggesting that mutant htt in glial cells affects glial function during aging and critically contribute to the age-dependent clinical phenotypes. We also found that in our GFAP-160Q HD transgenic mice, mutant htt can reduce BDNF release from astrocytes and cause demyelination or neuronal death reminiscent the pathological events in previous HD mouse models and human HD patient's brains. In this application, we propose three aims to investigate how expression of mutant htt in glial cells causes neuronal dysfunction and neurological phenotypes in HD transgenic mice. Aim 1 is to examine the effect of mutant htt on secretion of neurotrophic factors from glial cells. Aim 2 is to explore how mutant htt in glial cells causes age-dependent neurological phenotypes and neuropathology. Aim 3 is to investigate the protective effects of reducing htt in glial cells or improving glial function in HD mouse brains. These studies will help understand the mechanisms for age-dependent neuropathology in HD and the contribution of glial htt to HD pathology. Because glial cells are a desirable transplant population for therapy, the findings from our study may also provide a new therapeutic target for treating HD.