Genetic Analysis of Neurodegeneration

神经退行性疾病的遗传分析

• 批准号: 10665209
• 负责人: MEL B FEANY
• 金额: $ 92.17万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2031-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665209
• 关键词: Affect; Age; Alzheimer' s Disease; Ankyrins; Autophagosome; Autopsy; Binding; Biological Models; Caregivers; Cells; Complement; Cytoskeleton; Disease; Disease model; Drosophila genus; Gene Expression; Genes; Genetic Screening; Genetic Transcription; Goals; Healthcare; Modeling; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Parkinson Disease; Pathology; Patients; Play; Population; Resources; Role; Specificity; Spectrin; System; Testing; Therapeutic; Toxic effect; age related; alpha synuclein; beta Spectrin; brain tissue; cell type; dopaminergic neuron; effective therapy; fly; genetic analysis; genetic manipulation; genome-wide; innovation; neurotoxicity; synucleinopathy

Neurodegenerative diseases are common and devastating disorders, which will become increasingly prevalent as our population ages. Unfortunately, despite years of effort and some promising leads, we still do not have disease-modifying therapies. To provide an alternative approach to studying these disorders and identifying potential therapeutics we have pioneered the use of Drosophila as a model system for studying neurodegeneration, with a particular emphasis on Parkinson’s disease and Alzheimer’s disease. Our studies have allowed us to identify genes controlling neurodegeneration in our fly models. We have subsequently verified these findings in vertebrate models of the diseases, in postmortem brain tissue from patients and in patient-derived cells. In the current proposal we will capitalize on our prior progress by exploring in mechanistic detail the role alterations of the spectrin cytoskeleton play in promoting neurodegeneration in α-synucleinopathies. Specifically, we will test the hypothesis that α-synuclein binds to the ankyrin-binding domain of ß-spectrin and thereby perturbs autophagosome transport and maturation. We have recently developed a powerful new model of α-synuclein toxicity in Drosophila. Our previous model showed striking specificity for dopaminergic neurons. While valuable for exploring toxicity to dopamine neurons, a very important cell type for Parkinson’s disease, the restricted pathology present limited implementation of large-scale genetic screens. We have therefore created a model of α-synuclein neurotoxicity in which age-dependent neurodegeneration is significantly more widespread. Our new model has facilitated completion of a genome-scale genetic screen, an important strength of Drosophila models. Importantly, our new α-synucleinopathy model employs a dual transcriptional system we have developed, which allows simultaneous and independent manipulation of gene expression, at scale, in neurons and glia. We can now define the broad complement of mechanisms by which glia control toxicity of α-synuclein in neurons non-cell autonomously. Given the growing evidence for an important role for glia in neurodegenerative disease, these studies have the potential for significant impact.

神经退行性疾病是一种常见的破坏性疾病，它将变得越来越严重