Role of glia in LRRK2 mediated dopaminergic neuron degeneration

项目摘要 帕金森病（Parkinson's disease，PD）是一种神经退行性疾病，其特征是多巴胺能神经递质的进行性丢失。 神经元目前，在美国约有一百万人患有PD， 随着年龄的增长和老年人口的增加，患有这种疾病的人数 疾病预计在未来会增长。开发减缓或阻止疾病进展的靶向治疗 不仅能提高患者的生活质量，还能减轻社会的巨大经济负担。 LRRK2 G2019S是PD中最常见的错义突变，几种生物体，包括 果蝇，已被用来模拟LRRK2介导的神经变性。LRRK2 G2019 S改变神经突 形态学，并通过在果蝇多巴胺能神经元中表达LRRK2 G2019S，我们最近 表明它在体内诱导神经突长度和分支的年龄依赖性减少， 神经元缺失帕金森病研究的最新进展表明，PD不仅影响 神经元，但也神经胶质细胞的功能，使他们无法履行其生理作用， 维持组织内环境稳定并促进神经传递。研究吞噬细胞的确切作用 神经胶质细胞和星形胶质细胞在神经突丢失和神经元死亡中的作用是充分理解其机制的关键 导致神经退化在本提案的目标1中，我将研究神经胶质功能是否随着年龄的增长而改变。 突变LRRK2表达果蝇。在目标2中，我将评估抑制神经胶质功能是否会影响神经突丢失， 神经元死亡和运动功能，以及LRRK2 G2019S是否在LRRK2 G2019S果蝇中存在。 神经胶质导致或加剧神经变性。在目标3中，我将检查神经突的形态学变化， 结构导致突触的功能变化，以及这种表型是否对神经胶质细胞敏感。 活动：我将评估LRRK2 G2019S果蝇中不同年龄的突触数量，并使用函数 成像方法确定神经突损失是否转化为突触功能的改变。拟议 研究将检查神经突形态、突触功能和胶质吞噬细胞之间的关系。 活动，并提供神经胶质细胞在病理学中的作用机制的见解。研究结果将为 未来研究针对PD发展和进展的新干预措施。

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.