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Mechanistic analysis of axonal transport defects in motor neuron degenerative dis

运动神经元退行性疾病轴突运输缺陷的机制分析

基本信息

批准号：
8270484
负责人：
Erika L Holzbaur
金额：
$ 33.76万
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 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8270484
关键词：
Active Biological Transport Aging Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Automobile Driving Axon Axonal Transport Cell Death Cell model Cells Cessation of life Complex Data Defect Degenerative Disorder Disease Disease Progression Dynein ATPase Equilibrium Event Familial Amyotrophic Lateral Sclerosis Health Human Huntington Disease Inherited Intracellular Transport Kinesin Lead Link Mediating Microtubules Modeling Motor Motor Neuron Disease Motor Neurons Movement Mus Muscular Atrophy Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neurons Onset of illness Organelles Pathogenesis Pathway interactions Process Proteins Proteomics Relative (related person)Role Signal Transduction Signaling Molecule Testing Vesicle abstracting anterograde transport base cell motility dynactin insight motor neuron degeneration mouse model mutant protein degradation retrograde transport trafficking

项目摘要

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal and incurable disease characterized by the degeneration and death of motor neurons. Both sporadic and inherited forms of ALS follow a common pathogenic pathway, which is still not understood. One hypothesis that may explain the motor neuron-specific cell death observed in ALS and other similar neurodegenerative diseases is that motor neurons are uniquely sensitive to defects in axonal transport. Active transport along the axon is driven by microtubule motor proteins; while multiple kinesins drive anterograde transport, cytoplasmic dynein and its activator dynactin are the only motor driving retrograde transport. Dominant mutations in either dynein or dynactin are sufficient to cause motor neuron disease, demonstrating the importance of axonal transport in maintaining healthy motor neurons. We now have data directly demonstrating significant defects in retrograde transport in multiple models of motor neuron disease, including a well- characterized mouse model of familial ALS; defects in dynein localization and function occur as an early event in disease pathogenesis in these models. We will examine the mechanisms linking defects in axonal transport to neurodegeneration, focusing on alterations in both the efficiency of retrograde transport and the nature of the cargos being transported. We hypothesize that these changes act together to lead to alterations in the balance of survival and death signals in the neuron, resulting in neuronal degeneration and cell death. To test this hypothesis, we will pursue three specific aims. In Specific Aim 1, we will look at how dynein-mediated transport is altered during disease onset and progression. We will investigate the specific mechanisms involved by analyzing the motility of proteins and organelles isolated from mouse models of neurodegenerative disease. In Specific Aim 2, we will compare the cargos that are actively transported by dynein in wild type and degenerating neurons, using proteomic screens for dynein cargos. We hypothesize that changes in dynein cargos, especially signaling molecules, will result in alterations in the balance between survival and death signals. Finally, in Specific Aim 3, we will use cellular models of neurodegenerative disease to investigate how defects in axonal transport lead to neurodegeneration. We will examine the relative contributions of defects in the transport machinery and alterations in the cargo being transported, as well as defects in organelle trafficking and protein degradation. The studies proposed here will lead to a clearer understanding of the role of axonal transport in motor neuron degenerative disease. As disruption of intracellular trafficking has been observed in a growing number of degenerative and aging diseases, including Huntington's and Alzheimer's Disease, it is likely that the mechanistic studies proposed here will provide insights that are more broadly applicable to our understanding of neuronal degeneration. The active movement of proteins, vesicles, and organelles along the extended axons of neurons is called axonal transport. This transport is essential for the health and function of the neuron, and defects in the process cause motor neuron degeneration leading to muscle atrophy in diseases such as Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease). Here, we propose to investigate the mechanisms by which defects in axonal transport, caused either directly by mutations in the motor proteins that drive this transport, or indirectly by the expression of other mutant proteins, lead to degenerative disease.

摘要