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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.

项目总结