Role of glia in LRRK2 mediated dopaminergic neuron degeneration

胶质细胞在 LRRK2 介导的多巴胺能神经元变性中的作用

基本信息

批准号：
10602889
负责人：
Judit Pallos
金额：
$ 7.21万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10602889
关键词：
Ablation Address Affect Age Aging Apoptotic Architecture Astrocytes Axon Cause of Death Cell Death Cells Cessation of life Defect Development Disease Disease Progression Disease model Dopamine Drosophila genus Economic Burden Elderly Event Exhibits Foundations Functional Imaging Functional disorder Future Genetic Goals Homeostasis Hypertrophy Idiopathic Parkinson Disease Impairment In Vitro Intervention LRRK2 gene Late-Onset Disorder Lead Length Longevity Mediating Membrane Metabolic Microscopy Missense Mutation Modeling Monitor Morphology Motor Movement Disorders Mutation Nerve Degeneration Nervous System Neurites Neurodegenerative Disorders Neuroglia Neuronal Injury Neurons Organism Parkinson Disease Pathogenesis Pathologic Pathology Patients Persons Phagocytes Phagocytosis Phenotype Physiological Play Population Quality of life Reporter Research Risk Role Signal Transduction Societies Synapses Techniques Technology Temperature Testing Therapeutic Tissues Translating United States age related aged autosome calcium indicator disease phenotype dopaminergic neuron experimental study fly imaging approach improved in vivo insight mutant neuron loss neurotransmission novel novel therapeutic intervention novel therapeutics prevent receptor synaptic function tool

项目摘要

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.

项目概要帕金森病 (PD) 是一种神经退行性疾病，其特征是多巴胺能进行性丧失目前，美国约有 100 万人患有 PD，并且存在患 PD 的风险。随着年龄的增长，老年人口不断增加，患有这种疾病的人数预计该疾病在未来将会增长，开发减缓或阻止疾病进展的靶向治疗方法。不仅可以提高患者的生活质量，还可以减轻社会的巨大经济负担。 LRRK2 G2019S 是 PD 和多种生物体中最常见的错义突变，包括果蝇已被用于模拟 LRRK2 介导的神经变性，LRRK2 G2019S 会改变神经突。体外形态学，并通过在果蝇的多巴胺能神经元中表达 LRRK2 G2019S，我们最近研究表明，在明显的神经突形成之前，它会在体内诱导神经突长度和分支的年龄依赖性减少帕金森病研究的最新进展表明，帕金森病不仅影响神经元损失。神经元，而且神经胶质细胞的功能也受到影响，使它们无法履行其生理作用维持组织稳态并促进神经元传递研究吞噬细胞的精确作用。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在该提案的目标 1 中，我将检查神经胶质功能是否会因衰老而改变。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损失， 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 是否在在目标 3 中，我将检查神经突是否发生形态变化。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。研究将检查神经突形态、突触功能和神经胶质吞噬细胞之间的关系活动，并提供对神经胶质细胞在病理学中的作用的机制见解。这些结果将为以下方面提供基础：未来针对帕金森病发展和进展的新干预措施的研究。