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.

项目摘要帕金森氏病（PD）是一种神经退行性疾病，其特征是多巴胺能逐渐丧失神经元。目前，大约有100万人在美国居住在PD，并且有发展PD的风险随着年龄的增长而增加，老年人的人口正在增加，遭受这一困难的人数疾病预计将来会增长。开发较慢或停止疾病进展的有针对性治疗不仅会改善患者的生活质量，而且还将减少社会的巨大经济燃烧。 LRRK2 G2019S是PD中发现的最常见的错义突变，包括几种生物，包括果蝇已用于模拟LRRK2介导的神经变性。 LRRK2 G2019S改变神经蛋白体外形态，通过在蝇的多巴胺能神经元中表达LRRK2 G2019，我们最近有了表明它诱导了依赖年龄的神经蛋白长度和体内分支的减小，然后神经元损失。帕金森氏病研究的最新进展表明，PD不仅影响神经元，也是神经胶质细胞的功能，使他们无法履行其在维持组织内稳态并支持神经元传播。研究精确的吞噬作用神经胶质和星形胶质细胞在神经损失和神经元死亡中发挥作用是完全了解机制的关键导致神经变性。在此提案的目标1中，我将检查是否在衰老中改变胶质功能突变的LRRK2表达苍蝇。在AIM 2中，我将评估抑制神经胶质功能是否影响神经损失， LRRK2 G2019S苍蝇的神经元死亡和运动功能，以及LRRK2 G2019是否在神经胶质导致或加剧神经变性。在AIM 3中，我将检查神经蛋白的形态变化是否建筑导致突触时的功能变化，以及该表型是否对神经胶质敏感活动：我将评估LRRK2 G2019S苍蝇中跨年龄的突触的数量，并使用功能成像方法确定神经损失是否转化为突触功能的改变。提议研究将研究神经蛋白的形态，突触功能和神经胶质细胞之间的关系活动，并提供有关神经胶质在病理学作用的机械洞察力。结果将为未来对针对PD发展和进展的新干预措施的研究。