MOTOR NEURON DISEASE--NEUROPHYSIOLOGY AND PATHOLOGY

遗传性犬脊髓性肌萎缩症是一种 显性遗传性下运动神经元疾病 会导致虚弱、肌肉萎缩和瘫痪。临床上和 从病理上讲，HCSMA类似于 婴儿期和儿童期，并与其他 运动单位的形式系统功能演变严重影响 纯合子HCSMA个体。我们的结果突出了 神经肌肉传递缺陷在早期的重要性 HCSMA的软弱表现，表明 氨基吡啶类药物可短暂改善小鼠的运动能力 运动单位功能失调，提示运动可能起到作用 神经元活动本身导致运动单位功能障碍。我们现在 建议进行实验，重点研究其背后的机制 并研究细胞骨架异常可能导致的缺陷 与HCSMA的发病机制有关。我们将确定是否 在两个HCSMA中观察到的近端轴突异常 和人类运动神经元病(ALS)有关 运动部件性能不正常。我们将在体外使用 肌肉纤维记录、生命显微镜和荧光 进一步了解神经传递的染色方法 HCSMA的赤字以及这些赤字是否与结构性 肌肌交界处的变化。慢性电 刺激肌肉神经的作用将被用来检验 在确定运动单位功能障碍中的活动性。我们还研究了 神经丝磷酸化水平在多大程度上与 随着HCSMA临床虚弱的演变。HCSMA 模型继续提供独特的调查机会 运动神经元病的可能机制和 评估针对防止电机丢失的潜在解决方案 单位功能。

Hereditary Canine spinal Muscular Atrophy (HCSMA) is a dominantly inherited disorder of lower motor neurons which produces weakness, muscle atrophy, and paralysis. Clinically and pathologically, HCSMA resembles the spinal muscular atrophies of infancy and childhood and shares important features with other forms of motor units sysfunction evolves in severely affected homozygous HCSMA individuals. Our results highlight the importance of neuromuscular transmission deficits in the initial appearance of weakness in HCSMA, demonstrate that aminoopyridine drugs can improve transiently the performance of dysfunctional motor units and suggest a possible role for motor neuron activity itself in causing motor unit dysfunction. We now propose experiments that focus on mechanisms underlying these deficits and examine how cytoskeletal abnormalities may contribute to the pathogenesis of HCSMA. We will determine whether proximal axonal abnormalities that are observed in both HCSMA and human motor neuron disease (ALS) are associated with dysfunctional motor unit performance. We will use in vitro recording from muscle fibers, vital microscopy and fluorescent staining methods to gain further understanding of neurotransmission deficits in HCSMA and whether these are associated with structural changes at the meuromuscular junction. Chronic electrical stimulation of muscle nerves will be used to examine the role of activity in determining motor unit dysfunction. We also examine to what extent neurofilament phosphorylation levels are associated with the evolution of clinical weakness in HCSMA. The HCSMA model continues to provide unique opportunities to investigate possible mechanisms underlying motor neuron diseases and to evaluate potential solutions directed at preventing the loss of motor unit function.