Superoxide-sensitive radiotracer as a predictive biomarker of Parkinson's disease progression

项目总结 这一建议建立在几十年来支持线粒体功能障碍和 神经退行性疾病中的炎症。这项提议的目标是评估线粒体的潜力。 压力信号是预测帕金森氏病(PD)进展的生物标志物。我们的工作假设是 来自遗传和环境风险因素的集体压力影响线粒体动态平衡，诱导 免疫原性应激信号的释放，促使老化的大脑进入促炎状态。如果这些压力 如果信号得不到解决，高危受试者的氧化应激水平将持续高于 神经退行性变的阈值，最终导致帕金森病的临床表现。到目前为止，最早和 帕金森病患者线粒体应激信号大多是活性氧(ROS)的产生。其中一个关键是 线粒体ROS的信号功能是向细胞环境发出即将到来的生物能量应激的警报。 线粒体ROS直接激活小胶质细胞，增强其他线粒体损伤的免疫原性 相关模式(MtDAMP)和α-突触核蛋白在高危帕金森病脑中的表达。应激产生的初级ROS 线粒体和激活的小胶质细胞是超氧化物(O2~-)。因此，O2*-提供了线粒体和 免疫(有丝分裂免疫)应激。我们将确定这种有丝分裂免疫信号是否是帕金森病的关键驱动因素 第一个血脑屏障，O2*选择性PET探针，从关键字跟踪体内PD进展 在不同的动物模型中，从前驱到终末期的特征。我们的初步结果支持这一假设 高危帕金森病患者的基础氧化应激水平增加，这是[18F]ROStrace可以检测到的， 2)与帕金森病的进展相关；3)使转基因动物对与帕金森病相关的毒素敏感。我们现在 建议在已建立的具有特定先兆特征的帕金森病小鼠模型中验证这些发现 与丝裂免疫应激和α-突触核蛋白病理有关。前兆特征的进展将被监测 通过PET/MRI的多巴胺能信号的变化，睡眠-觉醒动力学，以及情绪的行为测试， 嗅觉、认知和自主神经功能，在多巴胺能神经元丧失引起的运动损伤之前。 这种方法将使我们能够研究有丝分裂免疫信号在模拟 帕金森病发病机制的复杂性在大多数晚发性患者中存在。我们的多层次、高度可翻译的战略 旨在确保这项研究直接应用于临床。

PROJECT SUMMARY This proposal builds on decades of evidence supporting a crucial role for mitochondrial dysfunction and inflammation in neurodegenerative disease. The goal of this proposal is to evaluate the potential of mitochondrial stress signals as predictive biomarkers of Parkinson’s disease (PD) progression. Our working hypothesis is that collective pressure from genetic and environmental risk factors impinges on mitochondrial homeostasis, inducing the release of immunogenic stress signals that drive the aging brain into a pro-inflammatory state. If these stress signals are not resolved, at-risk subjects will have a persistent elevation of oxidative stress that is above the threshold for neurodegeneration, ultimately leading to the clinical manifestation of PD. To date, the earliest and most established mitochondrial stress signal in PD is reactive oxygen species (ROS) production. One of the key signaling functions of mitochondrial ROS is to alert the cellular environment of impending bioenergetic stress. Mitochondrial ROS directly activate microglia, and boost the immunogenicity of other mitochondrial damage associated patterns (mtDAMPs) and α-synuclein in the at-risk PD brain. The primary ROS produced by stressed mitochondria and activated microglia is superoxide (O2*-). Thus, O2*- provides a signal of mitochondrial and immune (mito-immune) stress. We will determine if this mito-immune signal is a critical driver of PD using the first blood-brain barrier permeant, O2*- selective PET probe to track PD progression in vivo from the key prodromal features to the end stages in distinct animal models. Our preliminary results support the hypothesis that at-risk PD subjects have increased basal levels of oxidative stress that are 1) detectable by [18F]ROStrace, 2) correlate with PD progression, and 3) sensitize transgenic animals to toxins associated with PD. We now propose to validate these findings in established PD mouse models with prodromal features specifically related to mito-immune stress and α-synuclein pathology. The progression of the prodromal features will be monitored by changes in dopaminergic signaling via PET/MRI, sleep-wake dynamics, and behavioral tests of mood, olfaction, cognition, and autonomic function, prior to motor impairment caused by loss of dopaminergic neurons. This approach will allow us to investigate the role of mito-immune signaling in conditions mimicking the complexity of PD pathogenesis in the majority of late-onset patients. Our multi-tiered, highly translatable strategy is designed to ensure direct application of this research to the clinic.