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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.

项目总结