Glial huntingtin and neurodegeneration

 描述(申请人提供)：亨廷顿病(HD)代表一个依赖年龄的神经退行性疾病家族，包括阿尔茨海默氏症(AD)和帕金森氏症(PD)。这些疾病的特点是选择性神经变性，这是由年龄相关的错误折叠的蛋白质引起的。在HD中，疾病蛋白亨廷顿(HTT)携带一个扩大的多谷氨酰胺重复序列，在大脑中积累，随着患者年龄的增长形成聚集体，并导致进行性神经症状。鉴于HD的已知基因突变及其特征良好的神经病理学，HD是研究选择性神经病理学如何以年龄相关的方式发生的理想模型。以往的研究大多集中于突变型HTT对神经细胞的影响，并发现突变型HTT的N-末端片段发生错误折叠，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细胞，为神经细胞的生存和功能提供必要的支持。这些非神经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髓鞘蛋白用于轴突的髓鞘形成，而星形胶质细胞可以释放神经营养因子来支持神经元的生存和功能。然而，神经胶质细胞中突变的HTT是否会影响这些重要功能仍有待研究。我们已经建立了在星形胶质细胞(GFAP-160Q)或少突胶质细胞(PLP-150Q)中特异表达突变HTT的转基因小鼠模型。这两种HD小鼠模型都表现出年龄依赖性的神经学表型，这表明胶质细胞中突变的HTT在衰老过程中影响神经胶质功能，并对年龄相关的临床表型起关键作用。我们还发现，在我们的GFAP-160Q HD转基因小鼠中，突变的HTT可以减少星形胶质细胞释放BDNF，并导致脱髓鞘或神经元死亡，这让人想起以前HD小鼠模型和人类HD患者大脑的病理事件。在这项应用中，我们提出了三个目的来研究突变型HTT在胶质细胞中的表达如何导致HD转基因小鼠的神经元功能障碍和神经表型。目的1检测突变型hTt对神经胶质细胞分泌神经营养因子的影响。目的2是探索神经胶质细胞中突变的HTT是如何引起年龄依赖性神经表型和神经病理的。目的3：探讨HD患者降低胶质细胞HTT或改善胶质细胞功能的保护作用 老鼠的大脑。这些研究将有助于了解HD的年龄依赖性神经病理机制，以及胶质细胞HTT在HD病理中的作用。由于胶质细胞是治疗的理想移植人群，我们的研究结果也可能为HD的治疗提供一个新的治疗靶点。

 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.