Role of glia in LRRK2 mediated dopaminergic neuron degeneration

项目总结 帕金森病(PD)是一种以多巴胺能进行性丧失为特征的神经退行性疾病 神经元。目前在美国约有100万人患有帕金森病，并被视为发展为帕金森病的风险 随着年龄的增长和老年人口的增加，患有这种疾病的人数 预计疾病在未来还会增长。开发有针对性的治疗方法来减缓或阻止疾病的进展 不仅将提高患者的生活质量，还将减轻社会的巨大经济负担。 LRRK2 G2019S是PD中发现的最常见的错义突变，包括 果蝇，已经被用来模拟LRRK2介导的神经变性。LRRK2 G2019S改变轴突 通过在果蝇的多巴胺能神经元中表达LRRK2 G2019S，我们最近 结果表明，在活体实验中，它会导致神经突起长度和分支随年龄增长而缩短，而不是明显的 神经元丢失。帕金森氏病研究的最新进展表明，帕金森病不仅影响 神经元，但神经胶质细胞的功能，使它们无法履行其生理作用 维持组织的动态平衡，促进神经元的传递。探讨吞噬细胞的确切作用 胶质细胞和星形胶质细胞在轴突丢失中起作用，神经元死亡是全面了解其机制的关键。 导致神经退化。在这项提案的目标1中，我将检查在衰老过程中神经胶质功能是否发生改变 表达LRRK2的突变果蝇。在目标2中，我将评估抑制神经胶质功能是否会影响轴突丢失， LRRK2 G2019S果蝇的神经元死亡和运动功能随年龄的变化，以及LRRK2 G2019S是否在 神经胶质细胞导致或加剧神经变性。在目标3中，我将检查轴突的形态变化 结构导致突触的功能变化，以及这种表型是否对胶质细胞敏感 活动：我将评估LRRK2 G2019S果蝇不同年龄的突触数量，并使用功能性 影像方法确定轴突丢失是否会转化为突触功能的改变。建议数 研究将检查神经突起形态、突触功能和胶质细胞吞噬功能之间的关系。 活动，并提供了对胶质细胞在病理学中的作用的机械性洞察。研究结果将为以下工作奠定基础 未来针对帕金森病发生和进展的新干预措施的研究。

PROJECT SUMMARY Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons. Currently about one million people live with PD in the United States, and as the risk of developing PD increases with age and the population of the elderly is increasing, the number of people suffering from this disease is expected to grow in the future. Developing targeted treatments that slow or halt disease progression will not only improve patient quality of life, but would also reduce the vast economic burden on society. LRRK2 G2019S is the most common missense mutation found in PD, and several organisms, including Drosophila, have been used to model LRRK2-mediated neurodegeneration. LRRK2 G2019S alters neurite morphology in vitro, and by expressing LRRK2 G2019S in the dopaminergic neurons of flies, we have recently shown that it induces an age-dependent reduction of neurite length and branching in vivo, prior to overt neuronal loss. Recent advances in Parkinson's disease research have revealed that PD not only affects neurons, but also the function of glial cells, rendering them unable to fulfill their physiological role in maintaining tissue homeostasis and facilitating neuronal transmission. Investigating the precise role phagocytic glia and astrocytes play in neurite loss and neuronal death is key to fully understanding the mechanisms leading to neurodegeneration. In Aim 1 of this proposal I will examine whether glial function if altered in aging mutant LRRK2–expressing flies. In Aim 2 I will evaluate whether inhibiting glial function affects neurite loss, neuronal death, and motor function across age in LRRK2 G2019S flies, and whether LRRK2 G2019S in the glia leads to or exacerbates neurodegeneration. In Aim 3 I will examine if morphological changes in neurite architecture result in functional changes at the synapse, and whether this phenotype is sensitive to glial activity: I will evaluate the number of synapses across age in LRRK2 G2019S flies, and using a functional imaging approach determine if neurite loss translates into alterations in synaptic function. The proposed studies will examine the relationship between neurite morphology, synaptic function, and glial phagocytic activity, and offer mechanistic insight into the role of glia in pathology. The results will provide a foundation for future research into novel interventions against PD development and progression.