MOTOR NEURON DISEASE--NEUROPHYSIOLOGY AND PATHOLOGY

遗传性犬脊髓性肌萎缩症（HCSMA）是一种疾病

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.