Mechanism and importance of innate immune activation in a Drosophila GBA mutant model of Parkinson's disease

帕金森病果蝇 GBA 突变模型中先天免疫激活的机制和重要性

基本信息

  • 批准号:
    10039929
  • 负责人:
  • 金额:
    $ 23.33万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-10 至 2022-05-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT: Mutations in the glucosylceramidase beta (GBA) gene cause the lysosomal lipid storage disorder Gaucher’s disease and are the most frequent genetic association with Parkinson’s disease and Lewy body dementia. GBA encodes glucocerebrosidase, a lysosomal enzyme that catalyzes the breakdown of the sphingolipid glucosylceramide to ceramide and glucose. To explore the mechanism by which mutations in GBA predispose to these diseases, we created a Drosophila model of glucocerebrosidase deficiency by inactivating the Drosophila GBA ortholog, Gba1b. Gba1b mutants recapitulate many of the features of these diseases, including shortened lifespan, locomotor impairment, accumulation of glucosylceramide, protein aggregation in brain and other tissues, and neurodegeneration. In recently published work, we reported the results of a proteomic study of Drosophila Gba1b mutants that revealed dramatic alterations in the abundance and turnover of extracellular vesicle (EV) proteins. Our experiments also demonstrated that these proteomic findings reflected actual changes in the composition of EVs, and that genetic perturbations targeting factors involved in the production of EVs suppressed a Gba1b mutant phenotype. In more recent unpublished work, we used RNA-Seq to compare transcript abundance in Gba1b mutants and controls. This study revealed a profound induction of the innate immune response pathway in Gba1b mutants. This induction was specific to Gba1b mutants and was further corroborated in our proteomic data, and RNAi-mediated knockdown of an innate immune pathway component partially suppressed the brain protein aggregation phenotype of Gba1b mutants. From these and other findings, we hypothesize that the production of glucosylceramide-enriched EVs by Gba1b mutants triggers an innate immune response because these EVs resemble the glucosylceramide-enriched EVs released by pathogens during infection. We further hypothesize that this innate immune response accounts for the phenotypes of Gba1b mutants. We propose two aims to address these hypotheses; the first will investigate the mechanism of immune activation, and the second will investigate the importance of immune activation to Gba1b mutant pathogenesis. Thus, the primary goal of our research proposal is to provide a foundation for further mechanistic work by asking the two most fundamental questions raised by our preliminary findings: how does innate immune activation occur in Gba1b mutants, and is it important to their phenotypes? Given the increasing evidence for neuroinflammation in neurodegenerative disorders, including those caused by GBA mutations, we anticipate that our work will have broad medical significance.
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项目成果

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Leo J Pallanck其他文献

Leo J Pallanck的其他文献

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{{ truncateString('Leo J Pallanck', 18)}}的其他基金

Mechanism of innate immune activation in a Drosophila model of Alzheimer's disease related dementia
阿尔茨海默病相关痴呆果蝇模型中先天免疫激活机制
  • 批准号:
    10339866
  • 财政年份:
    2022
  • 资助金额:
    $ 23.33万
  • 项目类别:
Mechanism of innate immune activation in a Drosophila model of Alzheimer's disease related dementia
阿尔茨海默病相关痴呆果蝇模型中先天免疫激活机制
  • 批准号:
    10554427
  • 财政年份:
    2022
  • 资助金额:
    $ 23.33万
  • 项目类别:
Mechanism and importance of innate immune activation in a Drosophila GBA mutant model of Parkinson's disease
帕金森病果蝇 GBA 突变模型中先天免疫激活的机制和重要性
  • 批准号:
    10259742
  • 财政年份:
    2020
  • 资助金额:
    $ 23.33万
  • 项目类别:
Mechanisms of non-cell-autonomous regulation of brain protein aggregation in Drosophila
果蝇脑蛋白聚集的非细胞自主调节机制
  • 批准号:
    9791153
  • 财政年份:
    2018
  • 资助金额:
    $ 23.33万
  • 项目类别:
Therapeutic Potential of Small Molecule Activators of the PINK1-Parkin Pathway
PINK1-Parkin 通路小分子激活剂的治疗潜力
  • 批准号:
    8806805
  • 财政年份:
    2015
  • 资助金额:
    $ 23.33万
  • 项目类别:
A Drosophila model for studying mechanisms of Gaucher's disease and synucleinopathies
用于研究戈谢病和突触核蛋白病机制的果蝇模型
  • 批准号:
    9351579
  • 财政年份:
    2015
  • 资助金额:
    $ 23.33万
  • 项目类别:
Therapeutic Potential of Small Molecule Activators of the PINK1-Parkin Pathway
PINK1-Parkin 通路小分子激活剂的治疗潜力
  • 批准号:
    8996662
  • 财政年份:
    2015
  • 资助金额:
    $ 23.33万
  • 项目类别:
A proteomic approach to identify substrates of the AAA+ mitochondrial proteases
鉴定 AAA 线粒体蛋白酶底物的蛋白质组学方法
  • 批准号:
    9128054
  • 财政年份:
    2015
  • 资助金额:
    $ 23.33万
  • 项目类别:
A proteomic approach to identify substrates of the AAA+ mitochondrial proteases
鉴定 AAA 线粒体蛋白酶底物的蛋白质组学方法
  • 批准号:
    9015991
  • 财政年份:
    2015
  • 资助金额:
    $ 23.33万
  • 项目类别:
Mechanisms of somatic mtDNA mutation detection and elimination
体细胞线粒体DNA突变检测和消除机制
  • 批准号:
    8806928
  • 财政年份:
    2014
  • 资助金额:
    $ 23.33万
  • 项目类别:
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