Understanding cellular and molecular mechanisms of neurodegeneration

摘要 有效治疗神经退行性疾病的目标不仅需要理解内在的 神经元功能障碍，但非神经元细胞如何导致神经元功能障碍。脊髓小脑 共济失调1型(SCA1)是一种以变性为特征的致命性、显性遗传性神经退行性疾病 小脑中的浦肯野神经元。尽管人们高度关注神经元的内在机制，但其发病机制 SCA1尚不完全清楚，目前尚无有效的治疗方法可用于SCA1患者。 星形胶质细胞在神经元功能的几乎所有方面都发挥着基础作用，而在其他方面的研究 神经退行性疾病表明，它们在疾病的发病机制中起着重要作用。我们之前已经 在SCA1的小鼠模型中，小脑星形胶质细胞在症状前就被激活了，而且他们的 激活与神经元功能障碍和疾病进展相关。 我们的新的初步数据表明，星形胶质细胞在脑出血中具有双模式、疾病阶段依赖性作用。 SCA1的发病机制。我们已经发现，星形胶质细胞在症状前是有益的，而它们成为 症状出现后有害的。此外，我们还发现星形胶质细胞的这些不同作用是 受核因子-κB信号调节，是星形胶质细胞增生症的关键转录调节因子之一。我们还发现， 在疾病早期，NF-κB信号增强脑源性神经支持基因的表达 星形胶质细胞中的神经营养因子和钾通道Kir4.1，而在星形胶质细胞中，NF-κB减少 这些基因的表达。 这项提议的目的是检验我们的中心假设，即在疾病早期，星形胶质细胞中的NF-κB信号 调节神经保护性星形胶质细胞表型，但后期转向调节有害星形胶质细胞表型 疾病。我们认为，从机制上讲，NF-κB改变了星形胶质细胞的关键支持功能，如 促进神经元存活的能力(BDNF)，并维持细胞外离子和 神经递质(Kir4.1)以疾病特定阶段的方式表达。

ABSTRACT The goal to effectively treat neurodegenerative disorders will require an understanding not only of intrinsic neuronal dysfunction, but also of how non-neuronal cells contribute to neuronal dysfunction. Spinocerebellar ataxia type 1 (SCA1), is a fatal, dominantly inherited neurodegenerative disease characterized by degeneration of Purkinje neurons in the cerebellum. Despite intense focus on neuron intrinsic mechanisms, pathogenesis of SCA1 remains incompletely understood and there are no effective therapies available for SCA1 patients. Astroglia play fundamental roles in nearly all aspects of neuronal function, and research in other neurodegenerative diseases demonstrated that they contribute to disease pathogenesis. We have previously shown that cerebellar astroglia are activated pre-symptomatically in the mouse models of SCA1, and that their activation correlates with neuronal dysfunction and disease progression. Our new preliminary data indicate that astroglia have a bi-modal, disease-stage dependent role in the pathogenesis of SCA1. We have found that astroglia are beneficial pre-symptomatically, whereas they become harmful after the onset of symptoms. Moreover we have found that these different effects of astroglia are regulated by NF-κB signaling, one of the key transcriptional regulators of astrogliosis. We have also found that early in disease NF-κB signaling enhances the expression of neurosupportive genes brain derived neurotrophic factor (BDNF) and potassium channel Kir4.1 in astroglia, while later in SCA1, NF-κB decreases expression of these genes. The objective of this proposal is to test our central hypothesis that early in disease astroglial NF-κB signaling regulates neuroprotective astroglial phenotype, but switches to regulating harmful astroglial phenotype late in disease. We propose that mechanistically, NF-κB alters critical supportive functions of astroglia, such as the ability to promote neuronal survival (BDNF), and maintain homeostasis levels of extracellular ions and neurotransmitters (Kir4.1) in a stage-of disease specific manner.