Innovating high-resolution novel imaging approaches to elucidate mechanisms of prion-like spreadingof neurodegenerative disease

神经退行性疾病研究中一个令人兴奋的新领域是神经退行性疾病蛋白的Pron样传播现象。海绵状脑病的基础是基于蛋白质的感染性病原体，这一点已被证实。在这些罕见的，尽管是毁灭性的疾病中，Pron蛋白从正常的可溶形式转变为聚集的自我模板感染形式。这一过程引发了不可阻挡的病理传播和整个大脑的或有神经退化。但是，这种疾病机制是否会延伸到更多 常见的神经退行性疾病，如帕金森氏病(PD)、阿尔茨海默病和相关痴呆症？如果是这样的话，它代表着在理解疾病机制方面的游戏规则改变者，并为治疗开发开辟了许多新的途径。然而，任何对类病毒传播的治疗性或机械性研究都将需要开发强大的新成像方法来跟踪类病毒传播的路径，并了解这些蛋白质聚集体在传播时如何改变大脑功能。我们需要了解为什么他们会选择一些路线，而不是其他路线，以及这是如何影响大脑功能的。为了应对这一挑战，我们组建了一个跨学科团队，由一名工程师和一名遗传学家组成。首先，我们将使用最先进的大脑清理技术来获得 帕金森氏病蛋白α-突触核蛋白的类病毒蛋白繁殖的高分辨率图像。我们将监测这些聚集体从一个神经元扩散到下一个神经元的过程，追踪它们的路径。这些高分辨率的α-突触核蛋白传播的全脑3D地图将使我们能够识别与传播路径相关的基因表达模式，并为功能研究提名基因。然后，我们将利用先进的高分辨率光遗传功能磁共振成像(OfMRI)来揭示Pron样扩散对大脑网络活动和 同样，神经活动对类病毒传播的影响也是如此。我们的实验将为神经退行性疾病的普恩病毒样传播提供基本的机制洞察。我们应用的工具和我们学到的教训很可能广泛适用于神经退行性疾病，包括阿尔茨海默病和相关的痴呆症。

An exciting new area in neurodegenerative disease research is the emerging phenomenon of prion-like spreading of neurodegenerative disease proteins. Prions are well established as the protein-based infectious agent underlying the spongioform encephalopathies. In these rare, albeit devastating, diseases the prion protein converts from the normal soluble form to the aggregated self-templating infectious form. This process initiates an inexorable spread of pathology and contingent neurodegeneration throughout the brain. But could this disease mechanism extend to the more common neurodegenerative diseases like Parkinson’s disease (PD) and Alzheimer’s disease and related dementia? If so, it represents a game changer in terms of understanding disease mechanisms and opens many new avenues for therapeutic development. However, any therapeutic or mechanistic investigation into prion-like spreading will require the development of powerful new imaging approaches to track the path of prion-like spread and understand how these protein aggregates alter brain function as they spread. We will need to understand why they take some routes but not others and how this impacts brain function. To address this challenge, we have formed an interdisciplinary team, consisting of an engineer and a geneticist. First, we will use state of the art brain clearing technology to obtain high-resolution images of prion-like protein propagation of the Parkinson’s disease protein α-synuclein. We will monitor these aggregates as they spread from one neuron to the next, tracking their paths. These high-resolution brain wide 3D maps of alpha-synuclein spreading will empower us to identify gene expression patterns associated with spreading paths and to nominate genes for functional studies. Then, we will utilize advanced high-resolution optogenetic functional magnetic resonance imaging (ofMRI) to reveal the longitudinal effects of prion-like spreading on brain network activity and likewise the impact of neural activity on prion-like spreading. Our experiments will provide fundamental mechanistic insight into prion-like spread of neurodegenerative disease. The tools we apply and the lessons we learn will likely be broadly applicable to neurodegenerative diseases including Alzheimer’s disease and related dementias.