Understanding cellular and molecular mechanisms of neurodegeneration

了解神经退行性变的细胞和分子机制

• 批准号: 9915990
• 负责人: Marija Cvetanovic
• 金额: $ 33.05万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9915990
• 关键词: Astrocytes; Brain-Derived Neurotrophic Factor; Cells; Cerebellar Diseases; Cerebellum; Characteristics; Data; Development; Disease; Disease Progression; Electrophysiology (science); Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Homeostasis; Inherited; Ions; Knock-in; Mediator of activation protein; Modality; Molecular; Morphology; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neuronal Dysfunction; Neurons; Neurotransmitters; Nuclear; Onset of illness; Pathogenesis; Patients; Pharmacology; Phenotype; Play; Potassium; Potassium Channel; Preventive Intervention; Process; Regulation; Research; Role; Severity of illness; Signal Transduction; Symptoms; Testing; Therapeutic Intervention; Transgenic Organisms; Type 1 Spinocerebellar Ataxia; astrogliosis; ataxin-1; base; design; effective therapy; expectation; extracellular; genetic approach; improved; inward rectifier potassium channel; molecular pathology; motor behavior; motor deficit; mouse genetics; mouse model; mutant; neuronal survival; promoter; public health relevance; targeted treatment

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.

抽象的 有效治疗神经退行性疾病的目标不仅需要了解内在的 神经元功能障碍，还包括非神经元细胞如何导致神经元功能障碍。脊髓小脑 1 型共济失调 (SCA1) 是一种致命的、显性遗传的神经退行性疾病，其特征是退化 小脑中的浦肯野神经元。尽管人们强烈关注神经元的内在机制，但神经元的发病机制 SCA1 仍未完全被了解，并且没有针对 SCA1 患者的有效治疗方法。 星形胶质细胞在神经元功能的几乎所有方面以及其他领域的研究中都发挥着重要作用 神经退行性疾病表明它们有助于疾病的发病机制。我们之前有过 表明小脑星形胶质细胞在 SCA1 小鼠模型中症状发生前被激活，并且它们的 激活与神经元功能障碍和疾病进展相关。 我们的新初步数据表明，星形胶质细胞在疾病阶段具有双模式、依赖于疾病阶段的作用。 SCA1的发病机制。我们发现星形胶质细胞在症状发生前是有益的，而它们会变得 症状出现后有害。此外，我们发现星形胶质细胞的这些不同作用是 受 NF-κB 信号传导调节，NF-κB 信号传导是星形胶质细胞增生的关键转录调节因子之一。我们还发现 疾病早期 NF-κB 信号传导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 (BDNF) 和钾通道 Kir4.1，而随后在 SCA1 中，NF-κB 减少 这些基因的表达。 该提案的目的是检验我们的中心假设，即疾病早期星形胶质细胞 NF-κB 信号传导 调节神经保护性星形胶质细胞表型，但在晚期转而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，例如 促进神经元存活（BDNF）和维持细胞外离子稳态水平的能力 神经递质（Kir4.1）以疾病阶段特定的方式。