Global Intracellular Responses to Mitophagy

对线粒体自噬的整体细胞内反应

基本信息

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common age-related neurodegenerative diseases where patients display a loss of cognitive function with dementia. AD and PD both have neuropathological features widespread throughout the brain with protein aggregates made up of amyloid beta (Ab ) and a-synuclein, respectively. Although AD is associated with Ab and tau deposits, aggregated Lewy bodies in PD are comprised of a-synuclein and are also found in AD post-mortem tissue. Another commonality between these diseases is that dysfunctional mitochondria, which provide energy to neurons, are some of earliest detectable biochemical changes prior to excessive protein aggregation and neurodegeneration. Selective autophagy pathways specifically target worn out or damaged organelles or protein aggregates for degradation at the lysosome. However, why aren’t selective autophagy pathways such as mitophagy (removal of damaged mitochondria) and aggrephagy (removal of protein aggregates) able to recycle or keep up with the number damaged mitochondria and misfolded aggregated proteins in neurodegenerative diseases? The R35 parent award is working to understand how two biological processes: mitophagy and cell division are intimately linked. The understanding of interorganelle connectivity and mechanisms to coordinate diverse cell behaviors is lacking. To better understand the inheritance patterns of mitochondria during cell division, the parent grant aims to interrogate the mechanisms enabling communication between damaged mitochondria and centrosomes during mitosis. In this vein, one possible reason that mitophagy and aggrephagy mechanisms are not able to protect the cell is that their regulation is negatively linked by shared adaptor proteins required for both processes. Also, even though neurodegenerative disease aggregates such as TDP-43 and huntingtin are known to be cleared by aggrephagy, dementia related aggrephagy clearance mechanisms are understudied. This 1-year amendment application proposes to understand how mitophagy and aggrephagy are linked and either enhanced or inhibited when stimulated by the events that precede neurodegeneration. Using primary neurons exposed to a-synuclein preformed fibrils (PFF), we will induce a-synuclein aggregation and mitochondrial dysfunction. This supplement proposes to: Characterize the dynamic flux temporal between mitophagy and aggrephagy in PFF exposed neurons to determine their reliance on shared adaptor proteins. Perform quantitative proteomics to discover other key components to aggrephagy induced by PFFs in neurons. Use optical clearing in whole brains, to quantify aggregate formation and clearance by aggrephagy in PFF induced rodents genetically manipulating autophagy pathways. This 1-year proposal will build the foundational work for future proposals to understand mechanisms to manipulate mitophagy and aggrephagy to ensure both processes are working as efficiently as possible to delay the progression of dementia related neurodegenerative diseases.
项目总结

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The role of STING signaling in central nervous system infection and neuroinflammatory disease.
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Alicia M Pickrell其他文献

Alicia M Pickrell的其他文献

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{{ truncateString('Alicia M Pickrell', 18)}}的其他基金

Effects of SARS-CoV-2 Antiviral Ribonucleoside Analogues on Mitochondrial DNA
SARS-CoV-2 抗病毒核糖核苷类似物对线粒体 DNA 的影响
  • 批准号:
    10448062
  • 财政年份:
    2022
  • 资助金额:
    $ 41.8万
  • 项目类别:
Effects of SARS-CoV-2 Antiviral Ribonucleoside Analogues on Mitochondrial DNA
SARS-CoV-2 抗病毒核糖核苷类似物对线粒体 DNA 的影响
  • 批准号:
    10557154
  • 财政年份:
    2022
  • 资助金额:
    $ 41.8万
  • 项目类别:
Global Intracellular Responses to Mitophagy
对线粒体自噬的整体细胞内反应
  • 批准号:
    10264447
  • 财政年份:
    2021
  • 资助金额:
    $ 41.8万
  • 项目类别:
Global Intracellular Responses to Mitophagy
对线粒体自噬的整体细胞内反应
  • 批准号:
    10469574
  • 财政年份:
    2021
  • 资助金额:
    $ 41.8万
  • 项目类别:
Global Intracellular Responses to Mitophagy
对线粒体自噬的整体细胞内反应
  • 批准号:
    10631204
  • 财政年份:
    2021
  • 资助金额:
    $ 41.8万
  • 项目类别:
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