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

与路易体相关的所有痴呆症的共同特征是脑内神经元的积累和聚集。 在核周体和近端突起中有14kD的小蛋白α-突触核蛋白。CT的近端聚集- 疾病状态下的突触核蛋白与生理状态下的突触核蛋白非常不同， 主要位于远处的突触前部位。因此，病理条件导致的错误定位， α-突触核蛋白进入近端神经元隔室，除了蛋白质的积累/聚集之外。 虽然以前的许多研究都集中在导致o> 突触核蛋白进入不溶性原纤维，在终末期路易体中看到，关于突触核蛋白的作用知之甚少。 导致蛋白质近端错误定位的初始机制。由于α-突触核蛋白是在 神经元的胞体被运输到轴突，最终到达突触，我们的工作 假设是轴突运输和/或突触前靶向α-突触核蛋白的机制缺陷 是其在病理状态下错误定位的基础。为了验证这一假设，我们开发了一种新的 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 以及活神经元的轴突和终扣中α-突触核蛋白的突触前靶向。事实上， 在该系统中观察到病理形式的α-突触核蛋白的转运/靶向，支持我们的假设。 完成拟议的项目将提供深入了解这些疾病的初步病理机制， 痴呆症，也可能导致新的早期治疗目标。 相关性（参见说明）： 与路易体相关的痴呆是老年痴呆症的常见原因，仅次于 老年痴呆到目前为止，还没有已知的治疗方法。我们治疗这种疾病的最好方法是 然而，早期阶段，导致这些痴呆症的早期机制知之甚少。在这个项目中，我们 将通过确定一种关键蛋白质是如何在神经元中错位而导致疾病的，来解开这些早期事件。

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.