Axonal endo-lysosome transport mechanisms that regulate APP processing

调节 APP 加工的轴突内溶酶体转运机制

基本信息

  • 批准号:
    10431906
  • 负责人:
  • 金额:
    $ 41.88万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-09-30 至 2024-05-31
  • 项目状态:
    已结题

项目摘要

Our research will take a cell biology approach to investigate mechanisms controlling axonal lysosome transport and maturation. Through these efforts we will seek to define how defects in the axonal transport and maturation of lysosomes create a sub-cellular environment that is highly conducive to the amyloidogenic processing of APP and the development of amyloid plaque pathology. These efforts are motivated by human genetics studies that have identified multiple genes encoding endo-lysosomal pathway proteins as AD risk factors as well as the well established but poorly understood local accumulation of lysosomes within swollen axons that surround amyloid plaques. Although such lysosome accumulations are widely found in human AD brain tissue and are recapitulated in transgenic mouse models that develop amyloid plaques, the contributions of these lysosomes (either protective or deleterious) on disease progression or dementia are not known. Based on our previous investigation of the amyloid plaque-associated axonal lysosome accumulations and axonal lysosome transport mechanisms, we hypothesize that defects in axonal lysosome transport and maturation create hotspots for amyloidogenic APP processing. Therefore, to investigate the contribution of defective axonal lysosome transport to APP processing and Aβ peptide production, we aim to: (1) Define mechanisms that control axonal lysosome abundance; (2) Establish the impact of axonal transport defects on amyloid precursor protein processing, Aβ production and the development of amyloid plaque pathology. Central to these proposed studies is our recent discovery of a robust defect in the coordinated process of axonal lysosome transport and maturation in neurons from JNK-interacting protein 3 (JIP3) knockout mice. Through our proposed efforts to dissect the mechanisms whereby JIP3 regulates axonal lysosomes and their ability to serve as sites of APP processing, we will gain new insight into possible pathogenic roles played by these organelles in Alzheimer's disease. Focusing on this specific subcellular environment that is so supportive of the amyloidgenic processing of APP has the potential to identify new strategies to specifically suppress the most dangerous sub-cellular sites for APP processing while sparing potentially beneficial functions of genes such as APP, BACE1 and PSENs. This research could thereby lead to novel therapeutic opportunities focused on manipulating axon lysosome biogenesis and/or transport to limit both Aβ production and neuronal pathology. New insights into the cell biology of neuronal lysosomes revealed by the proposed studies are expected to have additional broad relevance to other neurodegenerative diseases with lysosomal contributions to their pathology such as Parkinson's disease, frontotemporal dementia and hereditary spastic paraplegia.
我们的研究将采用细胞生物学的方法来研究控制轴突溶酶体运输的机制。 和成熟。通过这些努力,我们将寻求定义轴突运输和 溶酶体的成熟创造了一个非常有利于淀粉样变的亚细胞环境。 APP的加工与淀粉样斑块病理的发展。这些努力是由人类推动的 遗传学研究发现编码内切溶酶体途径蛋白的多个基因是阿尔茨海默病的危险因素 因素,以及肿胀内溶酶体的局部堆积,虽然已建立,但了解甚少 围绕淀粉样斑块的轴突。尽管在人类阿尔茨海默病中广泛发现这种溶酶体积聚 脑组织,并在转基因小鼠模型中重复出现淀粉样斑块,这些贡献 这些溶酶体(无论是保护性的还是有害的)对疾病进展或痴呆症的影响尚不清楚。 基于我们先前对淀粉样斑块相关轴突溶酶体堆积的研究 和轴突溶酶体运输机制,我们假设轴突溶酶体缺陷 运输和成熟为淀粉样变性APP的加工创造了热点。因此,要调查 轴突溶酶体转运缺陷在APP加工和Aβ多肽生产中的作用 目的:(1)确定控制轴突溶酶体丰度的机制;(2)确定轴突对溶酶体丰度的影响 淀粉样前体蛋白加工、Aβ产生和淀粉样蛋白发育中的运输缺陷 斑块病理学。这些拟议研究的中心是我们最近发现的一个明显的缺陷 JNK相互作用蛋白3在神经元轴突溶酶体转运和成熟中的协调过程 (JIP3)基因敲除小鼠。通过我们提出的努力来剖析JIP3调节轴突的机制 溶酶体及其作为APP处理站点的能力,我们将获得新的见解 这些细胞器在阿尔茨海默病中所起的致病作用。专注于这个特定的亚细胞 如此支持APP淀粉样蛋白处理的环境有可能发现新的 专门抑制应用程序处理最危险的亚蜂窝站点的策略,同时节省 APP、BACE1和PSEN等基因的潜在有益功能。这项研究可能因此导致 新的治疗机会侧重于操纵轴突溶酶体的生物发生和/或运输以限制 Aβ产物和神经元病理学。对神经元溶酶体细胞生物学的新见解揭晓 通过拟议的研究,预计将与其他神经退行性疾病有更广泛的相关性 溶酶体在其病理中的作用,如帕金森氏病,额颞叶痴呆和 遗传性痉挛截瘫。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Efficient progranulin exit from the ER requires its interaction with prosaposin, a Surf4 cargo.
  • DOI:
    10.1083/jcb.202104044
  • 发表时间:
    2022-02-07
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Devireddy S;Ferguson SM
  • 通讯作者:
    Ferguson SM
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

SHAWN FERGUSON其他文献

SHAWN FERGUSON的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('SHAWN FERGUSON', 18)}}的其他基金

Axonal endo-lysosome transport mechanisms that regulate APP processing
调节 APP 加工的轴突内溶酶体转运机制
  • 批准号:
    10219145
  • 财政年份:
    2018
  • 资助金额:
    $ 41.88万
  • 项目类别:
Molecular mechanisms that match lysosome function to cellular demand
将溶酶体功能与细胞需求相匹配的分子机制
  • 批准号:
    8724530
  • 财政年份:
    2013
  • 资助金额:
    $ 41.88万
  • 项目类别:
Molecular mechanisms that match lysosome function to cellular demand
将溶酶体功能与细胞需求相匹配的分子机制
  • 批准号:
    8591993
  • 财政年份:
    2013
  • 资助金额:
    $ 41.88万
  • 项目类别:
Molecular mechanisms that match lysosome function to cellular demand
将溶酶体功能与细胞需求相匹配的分子机制
  • 批准号:
    10093058
  • 财政年份:
    2013
  • 资助金额:
    $ 41.88万
  • 项目类别:
Molecular mechanisms that match lysosome function to cellular demand
将溶酶体功能与细胞需求相匹配的分子机制
  • 批准号:
    10330554
  • 财政年份:
    2013
  • 资助金额:
    $ 41.88万
  • 项目类别:
Axonal Lysosome Dysfunction in Alzheimer's Disease
阿尔茨海默病中的轴突溶酶体功能障碍
  • 批准号:
    9086187
  • 财政年份:
  • 资助金额:
    $ 41.88万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了