The role of Rab1 GTPase and its activators in selective autophagy and neurodegenerative disease

Rab1 GTPase 及其激活剂在选择性自噬和神经退行性疾病中的作用

基本信息

  • 批准号:
    9225579
  • 负责人:
  • 金额:
    $ 19.99万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-09-30 至 2018-08-31
  • 项目状态:
    已结题

项目摘要

Abstract Age-related neurodegenerative diseases (ND), which affect the lives of millions of people, are caused by a progressive loss of neuronal function. This loss is associated with the accumulation of aggregated proteins, such as α-synuclein in Parkinson's disease and APP in Alzheimer's disease. The pathogenic mechanisms underling these diseases, for which currently there are no cures, are not fully understood. Autophagy, a cellular recycling pathway, shuttles excess and damaged cellular components to the lysosome for degradation. We propose that constitutive selective autophagy pathways clear ND-related protein aggregates. In mammalian cells, autophagy has been extensively studied under stress conditions, but almost nothing is known about constitutive selective autophagy processes or their regulation in human cells. Here, we propose to extend our recent studies in yeast about two types of constitutive selective autophagy pathways and their regulation by the Rab1 yeast homolog, Ypt1, to human cells. Rab1 GTPase was implicated in ND and its activation was proposed to inhibit accumulation of ND-related aggregates. However, Rab1 regulates both secretion and autophagy and it is not clear through which process its activation affects ND. Moreover, Rab1 activation in secretion was implicated in oncogenesis. Thus, to elucidate through which process Rab1 affects ND, it is crucial to separate its functions in secretion and autophagy. In yeast, we succeeded in separating the functions of Ypt1 in secretion and autophagy using two approaches: generating autophagy-specific Ypt1 mutations and characterizing autophagy-specific Ypt1 activators. These activators stimulate Ypt1 in two constitutive selective autophagy pathways: clearance of excess membrane proteins and clearance of cytoplasmic protein complexes. Because all the players are conserved from yeast to human cells, we propose to determine whether our findings pertain to human cells. In Aim 1, we will attempt to generate autophagy-specific Rab1 mutations and in Aims 2-3, we will determine whether autophagy-selective activators stimulate Rab1 in two distinct constitutive selective autophagy pathways. If successful, these tools will be used in future experiments to determine whether autophagy- specific Rab1 modulation affects clearance of ND-related protein aggregates. Achieving the goals of this proposal and the future experiments would provide a novel regulation paradigm for clearance of ND-related protein aggregates. Moreover, identification of Rab1 regulators specific for constitutive selective autophagy would provide novel ND therapeutic targets, in line with the missions of the National Institute of Neurological Disorders and Stroke.
摘要

项目成果

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Nava Segev其他文献

Nava Segev的其他文献

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{{ truncateString('Nava Segev', 18)}}的其他基金

Aberrant P-bodies accumulation and clearance in yeast and human cells.
酵母和人体细胞中异常 P 体的积累和清除。
  • 批准号:
    10551880
  • 财政年份:
    2022
  • 资助金额:
    $ 19.99万
  • 项目类别:
Aberrant P-bodies accumulation and clearance in yeast and human cells.
酵母和人体细胞中异常 P 体的积累和清除。
  • 批准号:
    10390634
  • 财政年份:
    2022
  • 资助金额:
    $ 19.99万
  • 项目类别:
Coordination of intracellular trafficking pathways by Ypt/Rab GTPases and their GEFs.
Ypt/Rab GTPases 及其 GEF 协调细胞内运输途径。
  • 批准号:
    10832932
  • 财政年份:
    2021
  • 资助金额:
    $ 19.99万
  • 项目类别:
Coordination of intracellular trafficking pathways by Ypt/Rab GTPases and their GEFs.
Ypt/Rab GTPases 及其 GEF 协调细胞内运输途径。
  • 批准号:
    10581959
  • 财政年份:
    2021
  • 资助金额:
    $ 19.99万
  • 项目类别:
Coordination of intracellular trafficking pathways by Ypt/Rab GTPases and their GEFs.
Ypt/Rab GTPases 及其 GEF 协调细胞内运输途径。
  • 批准号:
    10798944
  • 财政年份:
    2021
  • 资助金额:
    $ 19.99万
  • 项目类别:
Coordination of intracellular trafficking pathways by Ypt/Rab GTPases and their GEFs.
Ypt/Rab GTPases 及其 GEF 协调细胞内运输途径。
  • 批准号:
    10704918
  • 财政年份:
    2021
  • 资助金额:
    $ 19.99万
  • 项目类别:
Coordination of intracellular trafficking pathways by Ypt/Rab GTPases and their GEFs.
Ypt/Rab GTPases 及其 GEF 协调细胞内运输途径。
  • 批准号:
    10615724
  • 财政年份:
    2021
  • 资助金额:
    $ 19.99万
  • 项目类别:
Coordination of intracellular trafficking pathways by Ypt/Rab GTPases and their GEFs.
Ypt/Rab GTPases 及其 GEF 协调细胞内运输途径。
  • 批准号:
    10197424
  • 财政年份:
    2021
  • 资助金额:
    $ 19.99万
  • 项目类别:
Coordination of intracellular trafficking pathways by Ypt/Rab GTPases and their GEFs.
Ypt/Rab GTPases 及其 GEF 协调细胞内运输途径。
  • 批准号:
    10399615
  • 财政年份:
    2021
  • 资助金额:
    $ 19.99万
  • 项目类别:
ROLE OF YPT GTPASES IN INTRACELLULAR TRAFFICKING
YPT GTASE 在细胞内贩运中的作用
  • 批准号:
    7957793
  • 财政年份:
    2009
  • 资助金额:
    $ 19.99万
  • 项目类别:
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