In Vivo Optical Imaging of Alpha-Synuclein Aggregation

项目摘要 α-突触核蛋白聚集的体内光学成像 Kevin Webb，J. Chris Rochet和Jason Cannon，普渡大学 该项目需要应用高分辨率全脑光学分子成像方法来确定 帕金森病（Parkinson's disease，PD）发病机制的时空演变。PD 是一种使人衰弱的运动障碍，在全球范围内造成500万人死亡， 每年仅在美国就超过140亿美元。虽然大多数病例的原因尚不清楚， 环境和遗传因素与PD风险增加有关。异常聚集 突触前蛋白α-突触核蛋白（aSyn）被认为在PD发病机制中起关键作用。聚合是 假设发生在脑干的早期阶段，然后在大脑的特定区域的后期阶段 其中神经元损失或功能障碍导致主要运动症状。尽管这种机制 aSyn聚集在整个大脑中的迁移还不是很清楚，有证据表明细胞分泌 路是有牵连的。我们将在整个活体大脑中光学成像aSyn聚集的状态， 高空间分辨率和不同时间的aSyn表达，为实现迫切需要的目标提供了基础。 了解与PD发作和进展相关的知识。该方法将使用我们最近发现的一种方法， 从高度散射的光中形成具有前所未有的空间分辨率的图像， 在体内对荧光共振能量转移（FRET）进行成像。该项目的完成将使我们能够 对aSyn在整个大脑中传播的时间过程和程度以及 在活体动物模型中，传播的aSyn种类的聚集状态。了解PD进展的基础 将为在严重脑损伤发生之前的早期治疗提供机会。

Project Summary In Vivo Optical Imaging of Alpha-Synuclein Aggregation Kevin Webb, J. Chris Rochet, and Jason Cannon, Purdue University This project entails the application of a high resolution whole brain optical molecular imaging method to determine the pathogenic mechanism involved in the temporal and spatial development of Parkinson's disease (PD). PD is a debilitating movement disorder afflicting 5 million people worldwide that imposes an economic burden of more than $14 billion each year in the United States alone. While the causes of most cases are unknown, environmental and genetic factors have been repeatedly linked to increased PD risk. Abnormal aggregation of the presynaptic protein alpha-synuclein (aSyn) is thought to play a key role in PD pathogenesis. Aggregation is postulated to occur at an early stage in the brain stem, and then in later stages in specific areas of the brain where neuronal loss or dysfunction results in the cardinal motor symptoms. Although the mechanism by which aSyn aggregation migrates throughout the brain is not well understood, there is evidence that cell secretion pathways are involved. We will optically image states of aSyn aggregation throughout the whole living brain at high spatial resolution and at different times of aSyn expression, presenting a basis for achieving critically needed understanding related to PD onset and progression. The approach will use our recent discovery of a method to form images with unprecedented spatial resolution from highly scattered light and our earlier discovery of how to image fluorescence resonance energy transfer (FRET) in vivo. Completion of this project will enable us to extract critical insights into the time-course and extent of aSyn propagation throughout the brain, as well as the aggregation state of transmitted aSyn species, in a live animal model. Knowing the basis for progression of PD will provide opportunities for the development of early-stage treatment, before substantial brain damage occurs.