Inflammation and the Ubiquitin/Proteasome Pathway in Neurodegeneration.

神经变性中的炎症和泛素/蛋白酶体途径。

• 批准号: 7731801
• 负责人: MARIA Emilia FIGUEIREDO-PEREIRA
• 金额: $ 43.95万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7731801
• 关键词: 26S proteasome; 9-deoxy-delta-9-prostaglandin D2; Address; Adult; Alkylation; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Astrocytes; Binding; Brain; Cell Culture Techniques; Cell Death; Cell model; Cells; Chronic; Corpus striatum structure; Cysteine; Data; Disease model; Dopaminergic Cell; Dose; Event; Family; Glutathione; Goals; Human; Hydrolase; Inflammation; Inflammation Mediators; Inflammatory; Lead; Lewy Bodies; Link; Living Wills; Mediating; Microglia; Midbrain structure; Mitochondria; Modeling; Mus; Nerve Degeneration; Neuroblastoma; Neurodegenerative Disorders; Neuroglia; Neuronal Injury; Neurons; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Play; Post-Translational Protein Processing; Production; Prostaglandin D2; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Proteins; Publishing; Rattus; Reaction; Role; Series; Small Interfering RNA; Substantia nigra structure; Sulfhydryl Compounds; Therapeutic; Ubiquitin; Work; cyclopentenone; dopaminergic neuron; in vivo; male; molecular pathology; mouse model; multicatalytic endopeptidase complex; neuroinflammation; neurotoxic; nigrostriatal pathway; novel; prevent; progressive neurodegeneration; protein aggregate; protein aggregation; protein degradation; public health relevance; response; synuclein

DESCRIPTION (provided by applicant): Chronic inflammation is a critical factor in the pathogenesis of Parkinson's disease (PD). Neuronal and glial prostaglandins mediate proinflammatory responses, but there is a profound gap in our understanding of how cyclooxygenases and their prostaglandin products redirect cellular events to promote neurodegeneration. We propose studies to address this crucial omission. We will focus on inflammatory cyclopentenone prostaglandins, such as prostaglandin J2 (PGJ2), because they are potently neurotoxic. Our working hypothesis is that the "inflammatory mediator" PGJ2 plays a critical role in initiating progressive PD neurodegeneration. PGJ2 is derived spontaneously from PGD2, the major prostaglandin in the mammalian CNS. PGJ2 is a highly reactive and neurotoxic prostaglandin. PGJ2 is unique among the prostaglandin family because it covalently reacts with free sulfhydryls of glutathione and cysteine residues in cellular proteins, thus it is present in vivo primarily as Michael conjugates. Electrophile binding (S-alkylation) by endogenous compounds such as PGJ2 is regarded as playing an important role in determining whether neurons will live or die. We propose that this covalent protein modification by PGJ2 in the brain represents a novel pathogenic post-translational modification and plays a critical role in PD neurodegeneration. SPECIFIC AIM #1: Examine how PGJ2 causes ubiquitin/1-synuclein aggregation & its role in cell death Lewy bodies (LB) are a pathologic hallmark of PD. The major LB components are ubiquitinated proteins and 1-synuclein. The mechanisms leading to protein aggregation and its role in PD neurodegeneration remain unclear. We will investigate mechanisms induced by PGJ2 that lead to aggregation of ubiquitinated proteins/1- synuclein and cell death in (a) human dopaminergic-like neuroblastoma SK-N-SH cells, (b) rat ventral midbrain (dopaminergic) and (c) cortical neuronal cultures. Our experimental approach includes pharmacological manipulations and diminishing 1-synuclein expression by siRNA. These studies will characterize mechanisms by which PGJ2 causes PD neurodegeneration. SPECIFIC AIM #2: Characterize and optimize our novel PGJ2-induced model of Parkinson's disease The neuroinflammation hypothesis for PD is well accepted. However, there is still a profound gap in our understanding of how products of inflammation promote PD neurodegeneration. We established the first strong model in which an endogenous highly reactive product of inflammation, PGJ2, convincingly induces PD pathology. Our novel PGJ2-induced PD model strongly supports the hypothesis that localized and chronic production (by neurons and/or glia) of highly reactive and neurotoxic cyclopentenone PGJ2 establishes a link between neuroinflammation and PD neurodegeneration. By elucidating the neurotoxic events mediated by prostaglandins, we will be opening up new and important possible targets for pharmaceutical treatment of PD. PUBLIC HEALTH RELEVANCE: Chronic inflammation is a critical factor in the pathogenesis of Parkinson's disease (PD). The studies proposed in this application will elucidate mechanisms, such as alterations in intracellular protein turnover, by which products of inflammation contribute to neuronal injury. These studies are highly significant because a better understanding of the mechanisms by which products of inflammation mediate neuronal injury will lead to more effective anti-inflammatory therapeutic strategies for neurodegenerative disorders, such as PD that are associated with chronic inflammation.

描述（由申请人提供）：慢性炎症是帕金森病（PD）发病机制中的关键因素。神经元和神经胶质的前列腺素介导的促炎反应，但有一个深刻的差距，在我们的理解如何环氧合酶和它们的前列腺素产品重定向细胞事件，以促进神经退行性变。我们建议进行研究，以解决这一关键的遗漏。我们将重点关注炎症性环戊烯酮类化合物，如前列腺素J2（PGJ 2），因为它们具有强烈的神经毒性。我们的工作假设是，“炎症介质”PGJ 2在启动进行性PD神经变性中起着关键作用。PGJ 2自发地衍生自PGD 2，PGD 2是哺乳动物CNS中的主要前列腺素。PGJ 2是一种高反应性和神经毒性的前列腺素。PGJ 2在前列腺素家族中是独特的，因为它与细胞蛋白中谷胱甘肽和半胱氨酸残基的游离巯基共价反应，因此它主要作为迈克尔缀合物存在于体内。内源性化合物如PGJ 2的亲电结合（S-烷基化）被认为在决定神经元存活或死亡方面起重要作用。我们认为PGJ 2在大脑中的这种共价蛋白修饰代表了一种新的致病性翻译后修饰，并在PD神经变性中起着关键作用。具体目标#1：检查PGJ 2如何引起泛素/1-突触核蛋白聚集及其在细胞死亡中的作用路易体（LB）是PD的病理标志。LB的主要成分是泛素化蛋白和1-突触核蛋白。导致蛋白质聚集的机制及其在PD神经变性中的作用仍不清楚。我们将研究PGJ 2诱导的机制，该机制导致（a）人多巴胺能样神经母细胞瘤SK-N-SH细胞，（B）大鼠腹侧中脑（多巴胺能）和（c）皮质神经元培养物中泛素化蛋白/1-突触核蛋白的聚集和细胞死亡。我们的实验方法包括药理学操作和减少1-突触核蛋白表达的siRNA。这些研究将表征PGJ 2引起PD神经变性的机制。具体目标2：表征和优化我们新型的PGJ 2诱导的帕金森病模型PD的神经炎症假说已被广泛接受。然而，我们对炎症产物如何促进PD神经变性的理解仍然存在深刻的差距。我们建立了第一个强模型，其中内源性高反应性炎症产物PGJ 2令人信服地诱导PD病理。我们的新型PGJ 2诱导的PD模型强烈支持这样的假设，即局部和慢性生产（由神经元和/或神经胶质细胞）的高反应性和神经毒性的环戊烯酮PGJ 2建立了神经炎症和PD神经变性之间的联系。通过阐明野牡丹素介导的神经毒性事件，我们将为PD的药物治疗开辟新的和重要的可能靶点。公共卫生相关性：慢性炎症是帕金森病（PD）发病机制的关键因素。本申请中提出的研究将阐明炎症产物导致神经元损伤的机制，例如细胞内蛋白质周转的改变。这些研究非常重要，因为更好地了解炎症产物介导神经元损伤的机制将导致更有效的神经退行性疾病（如与慢性炎症相关的PD）的抗炎治疗策略。