Linking Synucleinopathy and Dysfunction of Olfactory Pathways

突触核蛋白病和嗅觉通路功能障碍之间的联系

• 批准号: 9978024
• 负责人: Patrik Brundin
• 金额: $ 56.04万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978024
• 关键词: 3-Dimensional; Affect; Anatomy; Antibodies; Autopsy; Binding; Brain; Brain region; Cell Death; Chronic; Clinical Research; Data; Detection; Deterioration; Development; Disease; Disease Progression; Economic Burden; Electron Microscopy; Electrophysiology (science); Functional disorder; Future; Immunohistochemistry; Immunotherapy; Impairment; Intervention; Knowledge; Lead; Lewy body pathology; Link; Macrophage Colony-Stimulating Factor Receptor; Measures; Mediating; Memory; Microglia; Microinjections; Mission; Molecular; Mus; National Institute on Deafness and Other Communication Disorders; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Odors; Olfactory Pathways; Outcome; Parkinson Disease; Pathogenesis; Pathogenicity; Pathology; Patients; Physiological; Physiology; Positioning Attribute; Procedures; Process; Public Health; Publishing; Research; Role; Smell Perception; Structure; Symptoms; System; Testing; United States National Institutes of Health; Wild Type Mouse; Work; alpha synuclein; awake; behavior test; design; experimental study; hyposmia; improved; in vivo; information processing; innovation; kinase inhibitor; motor disorder; motor symptom; neuroinflammation; neuron loss; neuropathology; novel; olfactory bulb; outcome prediction; piriform cortex; prevent; protein aggregation; relating to nervous system; response; synucleinopathy; therapeutic development

Project Summary/Abstract Hyposmia, the reduced ability to smell, is very common in Parkinson’s disease (PD). Almost 90% of PD patients have hyposmia, which often develops about a decade before motor symptoms manifest. The pathology of PD is characterized by the presence of aggregated α-synuclein in neurons across the brain; α-Synuclein aggregation is believed to start in the olfactory brain regions, especially the olfactory bulb, and then spreads to other structures in the brain. The manifestation of the symptoms in PD is therefore believed to reflect the spreading of the pathology, explaining why olfactory deficits would manifest before other symptoms. In addition to α-synuclein aggregation, there are other key processes that normally associate with PD – neuronal death and neuroinflammation. There is, however, a fundamental gap in knowledge regarding the pathogenic mechanisms which cause hyposmia in PD. Thus, the objective of this multi-PI project is to establish how the progressive spreading of aggregated α-synuclein from the olfactory bulb to other olfactory structures, and the associated neural cell death and neuroinflammation, trigger hyposmia. To this end, we will perform sophisticated measures of olfactory function (Wesson) in an experimental paradigm that we recently developed and which recreates spreading of α-synuclein pathology across olfactory structures associated with olfactory deficits (Brundin). With this approach we will define the links between olfactory dysfunction and key underlying mechanisms of early PD, testing the hypothesis that α- synuclein pathology progression from the olfactory bulb induces widespread neurodegeneration, protein aggregation, and neuroinflammation in the olfactory system, resulting in impaired olfaction. Specifically, we aim to demonstrate that α-synuclein pathology affects odor information processing and to identify neuropathological underpinnings of these olfactory deficits. Further, we will test innovative approaches to modulate pathogenesis and to determine whether these interventions can improve olfactory function and/or stop the spreading of the pathology. These findings will provide fundamental information on the olfactory system and on how olfaction is impacted by specific neurodegenerative processes. We expect that our findings will eventually facilitate the development of therapeutic approaches to prevent the development of olfactory deficits associated with the spreading of α-synuclein pathology across olfactory structures. Since these therapies should also prevent the spreading of α- synuclein pathology to other brain regions, they have the potential to become disease-modifying interventions against PD.

项目摘要/摘要 嗅觉减退是帕金森氏病(PD)的常见症状。近90%的帕金森病 患者患有性欲减退，通常在运动症状显现前大约十年出现。这个 帕金森病的病理特征是在整个大脑的神经元中存在聚集的α-突触核蛋白； α-突触核蛋白聚集被认为始于嗅脑区域，特别是嗅球， 然后扩散到大脑的其他结构。因此，帕金森病的症状表现为 被认为反映了病理的传播，解释了为什么嗅觉缺陷会在 其他症状。除了α-突触核蛋白聚集，还有其他关键过程，通常 与帕金森病-神经元死亡和神经炎症有关。然而，有一个根本性的差距， 了解导致帕金森病低血症的发病机制。因此，目标是 这个多PI项目是为了建立聚集的α-突触核蛋白如何从 嗅球到其他嗅觉结构，以及相关的神经细胞死亡和神经炎症， 触发低血症症。 为此，我们将在一项实验中执行复杂的嗅觉功能测量(Wesson 我们最近开发的一个范式，它重建了α-突触核蛋白病理的传播 与嗅觉缺陷相关的嗅觉结构(布伦丁)。使用此方法，我们将定义链接 嗅觉功能障碍和早期帕金森病的关键潜在机制之间的关系，验证了α- 来自嗅球的突触核蛋白病理进展导致广泛的神经变性，蛋白质 聚集，以及嗅觉系统中的神经炎症，导致嗅觉受损。 具体地说，我们的目标是证明α-突触核蛋白病理影响气味信息处理和 以确定这些嗅觉缺陷的神经病理基础。此外，我们将测试创新 调节发病机制和确定这些干预措施是否可以改善的方法 嗅觉功能和/或阻止病理传播。这些发现将为我们提供基本的 关于嗅觉系统以及特定神经退行性变如何影响嗅觉的信息 流程。我们期望我们的发现最终将促进治疗的发展。 预防与α-突触核蛋白传播相关的嗅觉缺陷的方法 嗅觉结构的病理学。因为这些疗法也应该防止α的传播- 突触核蛋白病理到其他大脑区域，它们有可能成为疾病修饰者 针对帕金森病的干预措施。