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氏病（AD）和帕金森氏病（PD）是最常见的与年龄有关的神经退行性的患者表现出痴呆症认知功能丧失的疾病。 AD和PD都有神经病理学特征在整个大脑中宽度，蛋白质聚集体由淀粉样蛋白β组成（AB）和A-突触核蛋白，尽管AD与AB和TAU沉积物相关，但总体Lewy PD中的身体已完成A-核蛋白，并且在AD后验尸组织中也发现。另一个普遍性在这些疾病之间，为神经元提供能量的功能失调的线粒体是在过量蛋白质聚集和神经变性之前，最早可检测到的生化变化。选择性自噬途径专门针对磨损或损坏的细胞器或蛋白质聚集体溶酶体的降解。但是，为什么没有选择性的自噬途径（例如删除）线粒体受损）和凝集（去除蛋白质聚集体）可以回收或跟上在神经退行性疾病中损坏的线粒体和错误折叠的聚集蛋白？ R35 父母奖正在努力了解两个生物学过程：线粒体和细胞分裂是密切的链接。对协调潜水细胞行为的机器间连通性和机制的理解是缺乏。为了更好地了解细胞分裂过程中线粒体的遗传模式，父母赠款的目标询问使线粒体和中心体之间沟通的机制在有丝分裂期间。在这种情况下，线粒体和敏锐的机制无法保护细胞的是，它们的调节是由两个过程所需的共享适配器蛋白负相关的。而且，即使神经退行性疾病骨料（例如TDP-43和Huntingtin）也是被敏锐的痴呆症相关的杂色清除机制清除。这1年修订申请提案，以了解线粒体和敏锐的链接并增强或在神经退行性之前的事件刺激时抑制。使用暴露于 A-突触核蛋白预先形成的原纤维（PFF），我们将诱导A-核蛋白聚集和线粒体功能障碍。这补充提案：表征PFF中线粒体和杂色之间暂时的动态通量暴露于神经元以确定它们对共享衔接蛋白的缓解。执行定量蛋白质组学发现神经元中PFF诱导的杂色的其他关键成分。在整个大脑中使用光学清除，量化PFF诱导的啮齿动物中的聚集体形成和清除率一般操纵自噬途径。这项为期1年的建议将建立基本工作，以便将来的建议了解操纵线粒体和敏锐的机制，以确保这两个过程的工作效率如此之高可能延迟痴呆症相关的神经退行性疾病的进展。