Axonal Transport and Presynaptic Targeting of Alpha-Synuclein in Pathological Sta

与路易小体相关的所有痴呆的一个共同特征是 核周和近端突起中的小14kD蛋白α-突触核蛋白。这种近端的ct堆积- 疾病状态下的突触核蛋白与生理状态非常不同，在生理状态下，蛋白质 主要定位于较远的突触前部位。因此，病理条件导致错误定位 除了蛋白质的聚集/聚集外，A-突触核蛋白还进入近端的神经元隔室。 虽然以前的许多研究都集中在导致O&GT聚集的生化过程； 融合核蛋白进入终末期路易小体中可见的不可溶的纤维中，但对 导致蛋白质近端错误定位的初始机制。因为α-突触核蛋白是在 神经细胞膜，并被运输到轴突，最终指向突触，我们的工作 假设轴突运输和/或突触前靶向α-突触核蛋白的机制存在缺陷 是其在病理状态下误定位的基础。为了验证这一假设，我们开发了一本小说 模型-系统和成像工具，使我们能够直接可视化和精确量化轴突运输 以及在活神经元的轴突和突触中的突触前靶向α-突触核蛋白。确实存在着缺陷 在这个系统中可以看到病理形式的α-突触核蛋白的运输/靶向，这支持了我们的假设。 拟议项目的完成将提供对这些疾病的初步病理机制的见解。 治疗痴呆症，也可能导致新的早期治疗靶点。 相关性(请参阅说明)： 与路易体相关的痴呆症是老年人痴呆的常见原因，仅次于 阿尔茨海默氏症。到目前为止，还没有已知的治疗方法。我们治疗这种疾病的最好机会是在一个 然而，在早期阶段，导致这些痴呆的早期机制还知之甚少。在这个项目中，我们 将通过确定关键蛋白质如何错位在神经元中而导致疾病来揭开这种早期事件。

A common feature in all dementias associated with Lewy Bodies is the accumulation and aggregation of the small 14kD protein a-synuclein in the perikaryon and proximal neurites. This proximal accumulation of ct- synuclein in diseased states is very different from the physiologic situation, where the protein is predominantly localized to distant presynaptic sites. Thus pathologic conditions lead to a mis-localization of a-synuclein into proximal neuronal compartments, in addition to the accumulation/aggregation of the protein. While many previous studies have focused on the biochemical processes leading to the aggregation of o> synuclein into the insoluble fibrils that are seen in the end-stage Lewy bodies, much less is known about the initial mechanisms that lead to the proximal mis-localization of the protein. As a-synuclein is synthesized in the neuronal perikarya and is transported into axons, eventually targeting to synapses, our working hypothesis is that defects in the mechanisms of axonal transport and/or presynaptic targeting of a-synuclein is the basis for its mis-localization in pathologic states. To test this hypothesis, we have developed novel model-systems and imaging tools that allow us to directly visualize and precisely quantify axonal transport and presynaptic targeting of a-synuclein in axons and boutons of living neurons. Indeed defects in transport/targeting of pathologic forms of a-synuclein are seen in this system, supporting our hypothesis. Completion of the proposed project will provide insights into initial pathologic mechanisms in these dementias, and may also lead to novel early therapeutic targets. RELEVANCE (See instructions): Dementias associated with Lewy bodies is a common cause of dementia among the elderly, second only to Alzheimer's. To date, there is no known cure. Our best chance of treating this disease is to attack it at an early stage, however, early mechanisms leading to these dementias is poorly understood. In this project we will unravel such early events by determining how a key protein gets misplaced in neurons, causing disease.