A MOTOR NEURON DEGENERATION MUTANT

人类神经系统疾病的动物模型可能对研究 各种病因学、结构-功能和药物测试研究。 遗传模型特别有吸引力，因为它们 生产大量的动物， 扰动，可以在不同阶段的研究， 疾病，与干预的可能性，使用未经治疗的 同窝仔作为对照。 一种迟发性遗传性运动神经元 最近，在C57B1/6小鼠亚系中发现了一种变性突变体， 识别并指定为Mnd。 这种疾病主要发生在 遗传，影响两性。 所有受影响的动物似乎 生育能力，虽然运动功能障碍限制繁殖后， 7-8月龄。 受影响的动物首先表现出虚弱， 后肢，后来在前肢，进展到严重 瘫痪 组织学是目前在两个较低和较高的 运动神经元 遗传学，迟发性症状， 病理学表明这是一个很好运动神经元 疾病，尤其是ALS。 本提案的重点是 前角运动神经元的形态学分析 脊髓和从脊髓发出的过程 （腹根轴突）。 动物的组织表现出不同的 疾病的程度将通过光和电子检查 显微镜 免疫细胞化学方法将用于 分析细胞骨架元素（神经丝，微管）， 脊髓运动神经元中存在大的胞质内含物 并描述神经递质含量的变化 合成酶ChAT。 形态测定分析 将用于评估运动神经元的大小和数量， 前根中轴突的密度和直径 与年龄和严重程度有关的脊髓区域 疾病 最后，将在disecrete中分析轴突运输 以确定是否有损害 运输 初步研究表明，这是一个损失，或在 至少在受影响的小鼠中出现了严重的微管重排。 这一建议的优势在于能够将 临床病理学与神经元结构的改变， 在特定时期肌肉结构的变化 疾病的进展。

Animal models of human neurological diseases may be useful for a variety of etiological, structure-function and drug testing studies. Hereditary models are particularly attractive because they produce substantial numbers of animals with reproducible perturbartions, that can be studied at different stages of the diesease, with the possibility of intervention using untreated littermates as controls. A late-onset, hereditary, motor neuron degeneration mutant in a C57B1/6 mouse substrain was recently identified, and designated Mnd. The disease is dominant in inheretance, affecting both sexes. All affected animals seem to be fertile, although the motor dysfunction restricts breeding after 7-8 months of age. Affected animals first exhibit weakness in the hindlimbs and later in the forelimbs, progressing to severe paralysis. Histopathology is present in both lower and upper motor neurons. The genetics, late-onset of symptoms and pathology suggest that this is a good molel of human motor neuron disease, especially that of ALS. The present proposal focuses on a morphological analysis of the motor neurons in the anterior horn of the spinal cord and of the processes that emanate from them (ventral root axons). Tissues from animals exhibiting different degrees of disease will be examined by light and electron microscopy. Immunocytochemical methods will be used to analyze cytoskeletal elements (neurofilaments, microtubules) in large cytoplasmic inclusions present in spinal cord motor neurons and to characterize changes in content of the neurotransmitter synthetic enzyme ChAT in those neurons. Morphometric analyses will be used to assess the size and number of the motor nerons and the density and diameters of axons in the ventral roots in given regions of the spinal cord in relation to age and severity of the disease. Lastly, axonal transport will be analyzed at disecrete stages of the disease to determine if there is compromised transport. Prelimminary studies suggest that here is a loss, or at least a severe rearrangement of microtubules in affected mice. The strength in this proposal lies in the ability to correlate clinical symptomology with alterations in neuron structure and with alterations in muslce structure at specific times in the progression of the diesease.