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Roles of Cdk5 in neurodevelopment and neurodegeneration

Cdk5 在神经发育和神经变性中的作用

基本信息

批准号：
7969705
负责人：
edward giniger
金额：
$ 54.48万
依托单位：
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7969705
关键词：
Adult Affect Aging Alzheimer&apos s Disease Animals Axon Behavioral Biological Models Birth Brain Brain region Cell Nucleus Cessation of life Characteristics Complex Cytoskeletal Proteins Defect Development Disease Drosophila genus Event Genes Genetic Head Histology Homologous Gene Human Invertebrates Lead Lesion Longevity Mammals Methods Modeling Molecular Genetics Morphology Motor Mus Muscle Rigidity Mutate Mutation National Institute of Neurological Disorders and Stroke Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neurofibrillary Tangles Neurons Neuropil Orthologous Gene Pathway interactions Patients Pattern Phosphotransferases Play Process Property Protein Kinase Proteins Role Structure Synapses Syndrome Tauopathies Tissues axon guidance base fly human disease interest mutant neural patterning neurodevelopment neuronal cell body neuronal survival notch protein null mutation prevent relating to nervous system response

项目摘要

How is the proper pattern of neural connections established during development? And how is that pattern maintained in the adult nervous system? These are the questions that the Axon Guidance and Neural Connectivity Unit seeks to answer. There is a great deal of interest in developing models of neurodegenerative diseases in simple, invertebrate model systems that provide unequaled experimental power for characterizing the cellular events of a complex process and establishing its molecular genetic basis. Use of Drosophila for studies of neurodegeneration have been problematic, however, since in general they have either relied on highly artificial manipulations, such as high-level expression of mutated human genes in the fly, or have identified genes that clearly affect neuronal survival in the fly but are not related to any gene or pathway demonstrated to play a role in neurodegeneration in mammals. We have now identified a natural, adult-onset neurodegenerative syndrome of Drosophila in flies mutant for the ortholog of a gene directly implicated in human diseases including Alzheimer Disease and ALS. The protein kinase Cdk5, together with its regulatory subunit, p35, is one of the major kinases that phosphorylates cytoskeletal proteins to generate the neurofibrillary tangles that are characteristic of the "tauopathy" class of neurodegenerative diseases. Moreover, activated Cdk5 is found concentrated in degenerating tissue in the brains of Alzheimer patients, and experimental activation of Cdk5 induces degenerating lesions in the mouse brain. We have generated a null mutation of the gene encoding the fly homolog of the Cdk5 activating subunit, p35. We find the mutants are viable and fertile, and are behaviorally normal at birth. However, within a few weeks they show progressive loss of motor coordination, culminating in rigidity and then death, with a significantly shortened lifespan (30% shorter than matched controls). Sectioning the heads of aging p35 mutant flies reveals degenerative lesions in the brain, initially in the neuropil but also around the cell bodies. Remarkably, these lesions are highly localized, being present bilaterally in specific brain nuclei, but not generally distributed through the brain, even though p35 and Cdk5 are present and active throughout the brain. Therefore, these mutants may allow us not only to uncover the genetic pathway leading to Cdk5-associated neurodegeneration, but also to understand how and why disease processes that occur throughout the brain lead to very specific and characteristic structural and behavioral defects in particular brain regions. Moreover, in mutant animals we observe widespread defects in axon patterning, synaptic morphology and protein localization within axons long before we see overt degeneration, raising the possibility that late onset degeneration may actually reflect a delayed response to defective nervous system structure early in development.

在发育过程中，正确的神经连接模式是如何建立的？这种模式是如何在成人神经系统中维持的呢？这些都是轴突引导和神经连接单元试图回答的问题。