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Synapse Loss in Spinal Muscular Atrophy

脊髓性肌萎缩症中的突触损失

基本信息

批准号：
7799701
负责人：
CHIEN-PING KO
金额：
$ 17.57万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-15 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7799701
关键词：
Age Axon Axosomatic Synapse Biochemical Cholinergic Receptors Defect Dendrites Development Disease Electron Microscopy Electrons Event Frequencies Future Gender Genetic Histology Infant Mortality Label Lead Light Measures Microglia Microscopic Morphology Motor Neurons Mus Muscle Muscle Fibers Muscular Atrophy Nerve Neuromuscular Junction Neurons Onset of illness Pathogenesis Pattern Presynaptic Terminals Process Proprioceptor Proteins Research Rest Schwann Cells Sensory Severities Site Spinal Spinal Cord Spinal Ganglia Spinal Muscular Atrophy Synapses Synaptic Vesicles Testing Thinking Type II Spinal Muscular Atrophy Western Blotting congenic density infant death motor impairment mouse model mutant nerve supply nervous system disorder neuronal cell body novel novel therapeutics postsynaptic presynaptic public health relevance receptor response

项目摘要

DESCRIPTION (provided by applicant): Proximal Spinal Muscular Atrophy (SMA), a leading genetic cause of infant mortality, is an autosomal recessive disease characterized by the loss of spinal motoneurons, muscle atrophy, and motor impairments with varying disease onset and severity (type I is severe; type II, moderate; type III, mild). Currently, there is no cure for this devastating neurological disease, and the mechanisms of the pathogenesis of SMA are not well understood. In this application, type II SMA-like mouse models (SMN 7 SMA and SMN-Hung SMA) will be used to test a novel concept that reduction of synaptic inputs to motoneurons in the spinal cord, instead of degeneration of neuromuscular junctions, is the key event contributing to motor impairments. Aim 1 will test the hypothesis that the neuromuscular junction is not the major site of defects in type II SMA mice. Light and electron microscopy, as well as electrophysiological analyses, will be applied to examine whether neuromuscular junctions in type II SMA mice at various ages are innervated and function normally, as compared with age- and gender-matched non-SMA littermates. Aim 2 will test the hypothesis that synaptic inputs onto spinal motoneurons are reduced in type II SMA mice. Morphological and biochemical analyses will be used to compare numbers of synaptic puncta on spinal motoneurons and the expression of synaptic vesicle proteins in the spinal cord in type II SMA with those in age- and gender-matched non-SMA littermates. Whether the synapse loss involves synaptic stripping by microglia also will be examined. In addition, whether the synaptic defects are attributed to a decrease or degeneration of synaptic inputs from proprioceptive sensory neurons in the dorsal root ganglion will be investigated. The findings of the proposed research will provide a new concept that SMA is a disease of synapse loss in the spinal motoneurons, rather than degeneration of neuromuscular junctions, as suggested by the prevailing thinking. The proposed research is thus relevant to the development of novel therapies for SMA by targeting synaptic defects in the spinal cord. The new therapeutic concept could be applied to treat other types of motoneuron diseases. PUBLIC HEALTH RELEVANCE: The proposed research is highly relevant to Spinal Muscular Atrophy (SMA), a leading genetic cause of infant death characterized by motor impairments and the loss of motor neurons in the spinal cord. We will use mouse models mimicking type II (moderate) SMA to test a novel concept that synapse loss in spinal motoneurons is a key event contributing to motor impairments. The proposed research would lead to future development of novel therapies for SMA by targeting synaptic defects in the spinal cord.

描述（由申请方提供）：近端脊髓性肌萎缩症（SMA）是婴儿死亡的主要遗传原因，是一种常染色体隐性遗传疾病，其特征为脊髓运动神经元缺失、肌肉萎缩和运动障碍，具有不同的疾病发作和严重程度（I型为重度; II型为中度; III型为轻度）。目前，对于这种毁灭性的神经系统疾病没有治愈方法，并且SMA的发病机制还不清楚。在本申请中，II型SMA样小鼠模型（SMN 7 SMA和SMN-Hung SMA）将用于测试一个新概念，即脊髓运动神经元的突触输入减少而不是神经肌肉接头变性是导致运动损伤的关键事件。目的1将检验神经肌肉接头不是II型SMA小鼠缺陷的主要部位的假设。将应用光学和电子显微镜以及电生理学分析，以检查与年龄和性别匹配的非SMA同窝小鼠相比，不同年龄的II型SMA小鼠的神经肌肉接头是否神经支配和功能正常。目的2将检验在II型SMA小鼠中脊髓运动神经元上的突触输入减少的假设。将使用形态学和生化分析比较II型SMA与年龄和性别匹配的非SMA同窝仔中脊髓运动神经元上的突触点数量和脊髓中突触囊泡蛋白的表达。突触丢失是否涉及小胶质细胞的突触剥离也将被检查。此外，突触缺陷是否归因于背根神经节中本体感受感觉神经元的突触输入的减少或退化将被研究。拟议研究的结果将提供一个新的概念，即SMA是一种脊髓运动神经元突触丢失的疾病，而不是流行思想所建议的神经肌肉接头变性。因此，拟议的研究与通过靶向脊髓中的突触缺陷来开发SMA的新型疗法相关。这一新的治疗理念可应用于其他类型的运动神经元疾病的治疗。公共卫生相关性：这项研究与脊髓性肌萎缩症（SMA）高度相关，SMA是婴儿死亡的主要遗传原因，其特征是运动障碍和脊髓运动神经元的丧失。我们将使用模拟II型（中度）SMA的小鼠模型来测试一个新的概念，即脊髓运动神经元中的突触丢失是导致运动障碍的关键事件。拟议的研究将通过靶向脊髓中的突触缺陷，导致SMA新疗法的未来发展。