Linking Synucleinopathy and Dysfunction of Olfactory Pathways

项目总结/摘要 嗅觉减退，即嗅觉能力下降，在帕金森病（PD）中非常常见。几乎90%的PD 病人有嗅觉减退，通常在运动症状出现前十年左右出现。的 PD的病理特征是大脑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，PD的症状表现为 据信反映了病理学的传播，解释了为什么嗅觉缺陷会在 其他症状。除了α-突触核蛋白的聚集，还有其他的关键过程， 与PD相关-神经元死亡和神经炎症。然而，在以下方面存在着根本性的差距： 了解导致PD嗅觉减退的致病机制。因此， 这个多PI项目是为了确定聚集的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， 引发嗅觉减退 为此，我们将在一个实验中进行嗅觉功能（韦森）的复杂测量。 这是我们最近开发的一个范例，它再现了α-突触核蛋白病理学在整个 与嗅觉缺陷相关的嗅觉结构（Brundin）。通过这种方法，我们将定义链接 嗅觉功能障碍和早期PD的关键潜在机制之间的关系，检验α- 来自嗅球的突触核蛋白病理学进展诱导广泛的神经变性，蛋白质 聚集和嗅觉系统中的神经炎症，导致嗅觉受损。 具体来说，我们的目标是证明α-突触核蛋白病理学影响气味信息处理， 以确定这些嗅觉缺陷的神经病理学基础。此外，我们将测试创新 调节发病机制的方法，并确定这些干预措施是否可以改善 嗅觉功能和/或阻止病理的扩散。这些发现将提供基本的 关于嗅觉系统以及嗅觉如何受到特定神经退行性疾病影响的信息 流程.我们希望我们的研究结果最终将促进治疗药物的开发。 预防与α-突触核蛋白扩散相关的嗅觉缺陷发展的方法 嗅觉结构的病理学。由于这些疗法也应该防止α- 突触核蛋白病理学的其他大脑区域，他们有可能成为疾病修饰 针对PD的干预措施。

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.