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Global Intracellular Responses to Mitophagy

对线粒体自噬的整体细胞内反应

基本信息

批准号：
10707665
负责人：
Alicia M Pickrell
金额：
$ 41.8万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-13 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10707665
关键词：
Adaptor Signaling Protein Alzheimer&apos s Disease Alzheimer&apos s disease brain Amendment Amyloid beta-Protein Autophagocytosis Autopsy Award Biochemical Biological Process Brain Cell division Cell physiology Cells Centrosome Communication Complex Cytoprotection Dementia Deposition Deterioration Diagnosis Diagnostic Disease Ensure Event Excision Exposure to Funding Future Genes Huntington gene Impaired cognition Inheritance Patterns Lewy Bodies Lewy body pathology Link Lysosomes Mitochondria Mitochondrial Proteins Mitosis Molecular Motor Mus Nerve Degeneration Neurodegenerative Disorders Neurons Optics Organelles Parents Parkinson Disease Pathogenicity Pathology Pathway interactions Patients Phosphotransferases Population Positioning Attribute Predisposition Process Proteomics Recycling Regulation Reporting Research Rodent Signal Transduction System Techniques Tissues Veins Work age related neurodegeneration alpha synuclein cell behavior cognitive function fluorophore genetic manipulation in vivo live cell imaging misfolded protein mitochondrial dysfunction multicatalytic endopeptidase complex neuropathology parent grant phosphoneuroprotein 14 pre-formed fibril programs protein TDP-43 protein aggregation response synuclein tau Proteins

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.

项目摘要阿尔茨海默病（AD）和帕金森病（PD）是最常见的年龄相关性神经退行性疾病患者表现出认知功能丧失伴痴呆的疾病。AD和PD都有神经病理学特征广泛分布于整个大脑，具有由淀粉样β蛋白组成的蛋白质聚集体 (Ab）和α-突触核蛋白。虽然AD与Ab和tau沉积物有关，但聚集的Lewy PD中的小体由α-突触核蛋白组成，并且也在AD死后组织中发现。另一个共性为神经元提供能量的线粒体功能失调，在过度蛋白质聚集和神经变性之前最早可检测到的生化变化。选择性自噬途径特异性靶向磨损或受损的细胞器或蛋白质聚集体，在溶酶体降解。然而，为什么选择性自噬途径，如线粒体自噬（去除），受损的线粒体）和聚集（蛋白质聚集体的去除）能够回收或跟上神经退行性疾病中受损的线粒体和错误折叠的聚集蛋白的数量？R35 父母奖致力于了解两个生物过程：线粒体自噬和细胞分裂是如何密切相关的有联系对细胞器间连接和协调不同细胞行为的机制的理解是缺乏为了更好地理解线粒体在细胞分裂过程中的遗传模式，研究受损线粒体和中心体之间的通讯机制，在有丝分裂期间。在这种情况下，一个可能的原因是线粒体自噬和聚集性吞噬机制不能保护细胞的一个重要原因是，它们的调节通过两个过程所需的共享衔接蛋白负相关。此外，即使已知神经退行性疾病聚集体如TDP-43和亨廷顿蛋白与神经退行性疾病聚集体相关，通过聚集性吞噬清除，痴呆相关的聚集性吞噬清除机制正在研究中。该1年修正案申请提出了解线粒体自噬和聚集性自噬是如何联系在一起的，或者在受到神经变性之前的事件刺激时被抑制。使用暴露于 α-突触核蛋白预形成纤维（PFF），我们将诱导α-突触核蛋白聚集和线粒体功能障碍。这补充建议：表征PFF中线粒体自噬和聚集性自噬之间的动态流量时间暴露的神经元，以确定它们对共享适配器蛋白的依赖。进行定量蛋白质组学，发现PFF在神经元中诱导的聚集吞噬的其他关键成分。在整个大脑中使用光学清除，通过PFF诱导的啮齿动物中的聚集吞噬作用定量聚集体形成和清除，自噬途径这份为期一年的提案将为未来的提案奠定基础，操纵线粒体吞噬和聚集吞噬的机制，以确保这两个过程都能有效地工作，可能延缓痴呆相关神经退行性疾病的进展。