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Dynamics of Axonal Autophagy in Neurons

神经元轴突自噬的动力学

基本信息

批准号：
10223588
负责人：
Erika L Holzbaur
金额：
$ 42.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10223588
关键词：
Ablation Address Aging Autophagocytosis Autophagosome Axon Axonal Transport Back Biochemical Caenorhabditis elegans Cells Cellular biology Complex Computer Models Cytoplasmic Protein Defect Degradation Pathway Disease Drosophila genus Dynein ATPase Eating Ensure Genes Health Homeostasis Human Huntington Disease Huntington gene In Vitro Intracellular Transport Lead Length Longevity Lysosomes Maintenance Microscopy Microtubules Mitochondria Modeling Molecular Motor Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Organelles Parkinson Disease Pathway interactions Patients Play Presynaptic Terminals Process Proteomics Recycling Resolution Role Route Site Stress Synapses Therapeutic Work axonal degeneration biophysical techniques cell type dynactin in vitro Assay in vivo induced pluripotent stem cell insight late endosome live cell imaging meter mitochondrial dysfunction mouse model mutant neuronal cell body novel therapeutic intervention presynaptic protein aggregation retrograde transport stressor superoxide dismutase 1 uptake

项目摘要

Project Summary Autophagy is an essential cellular degradative pathway triggered by environmental stress in many cell types. In neurons, autophagy has a further role as a constitutively active mechanism that maintains axonal homeostasis. In vitro and in vivo, autophagosomes are generated de novo at axon terminals and synaptic sites. Once formed, axonal autophagosomes are trafficked back to the soma by the retrograde microtubule motor protein cytoplasmic dynein. Autophagosomes mature en route through fusion with late endosomes and lysosomes. Cargo degradation also occurs during transport along the axon, leading to the somal delivery of digested contents for recycling in new biosynthetic pathways. Axonal autophagy degrades mitochondrial fragments and disease- associated protein aggregates, suggesting a key role in the maintenance of axonal homeostasis. Consistent with this hypothesis, neuron-specific ablation of autophagy is sufficient to cause neurodegeneration. However, many outstanding questions remain that must be addressed: How is autophagy regulated in neurons? What controls the localization and timing of autophagosome formation and cargo engulfment? What is the function of axonal autophagy – what cargos are targeted for degradation, and by what mechanisms? And how does the axonal autophagy pathway intersect with the endolysosomal pathway to effectively degrade cargos such as dysfunctional organelles and aggregated proteins? To address these questions, we will use live cell imaging in primary neurons and gene-edited iPSC-derived human neurons, in concert with biochemical and biophysical approaches including proteomic analysis and computational modeling, to query the basic mechanisms of axonal autophagy and how these mechanisms are perturbed by neuronal stressors including mitochondrial dysfunction, protein aggregation, and lysosomal damage. We will address the following specific aims: Aim 1: How is autophagy spatially and temporally regulated in neurons? What controls the initiation of autophagy at the axon terminal or presynaptic sites? Aim 2: What cargos are degraded by axonal autophagy? Is cargo engulfment a selective process, or nonspecific? Is there preferential uptake of some cargos, and if so, what are these cargos? What mechanisms control cargo uptake? And Aim 3: How does the autophagy pathway intersect with the lysosomal pathway? How is autophagosome-lysosome fusion regulated? Why is axonal autophagy so dependent on retrograde axonal transport? And what mechanisms regulate lysosomal health along the axon, as lysosomes are required for the effective clearance of engulfed cargos by autophagy. Given the essential and conserved role that autophagy plays in neurons, we anticipate that these studies will significantly advance our understanding of neuronal cell biology, providing important insights into the mechanisms maintaining axonal. homeostasis and how the perturbation of these mechanisms may lead to neurodegeneration. We hope that these advances will provide new ideas on how to best intervene therapeutically to treat diseases such as ALS, Huntington's, and Parkinson's disease.

项目总结