SELECTIVE NEURONAL INVOLVEMENT IN MOTOR NEURON DISEASE

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The reason why certain motor neurons are severely affected in motor neuron disease, such as amyotrophic lateral sclerosis (ALS), while others are spared, is entirely unknown. A large gap in the current knowledge on this issue needs to be filled, since the underlying mechanism may relate to the pathogenesis of motor neuron degeneration. We have an opportunity to investigate this mechanism by using the wobbler mouse, an animal with hereditary motor neuron disease. The nature of this motor neuron disease has been extensively studied and considered a valuable model for the investigation of motor neuron disease processes. The wobbler mouse presents with unique features of selective neuronal involvement: cervical motor neurons are affected but lumbar motor neurons are spared. Despite the fact that the pathological process of this motor neuron disease is a primary neuronopathy, axonal regeneration occurs in response to both spontaneous axonal degeneration and axotomy. Axonal regeneration may be a key process for compensating against motor neuron degeneration. We aim, by comparing wobbler mice to their normal littermates, to: (1) determine whether the difference in the two groups of motor neurons is due to different regenerative capacity; (2) determine whether this difference is based on differences in RNA and/or protein synthesis; (3) determine whether the difference in regenerative capacity is based on differences in fast axonal transport; (4) determine whether the difference in regenerative capacity is based on differences in slow axonal transport. Axonal transport techniques will be applied to analyze quantitatively axonal regeneration after nerve crush and to quantify the amount and rate of fast and slow axonal transport both before and after axotomy. Changes in polypeptide composition will be studied by polyacrylamide-gel-electrophoresis and fluorography. With retrograde axonal transport techniques, the time interval required for regenerating axons to arrive at the muscle will be determined. Neuronal RNA and protein synthesis will be measured by quantitative autoradiography. This analysis of neuronal functions in both differently affected motor neurons and the same groups of motor neurons in healthy animals will ultimately lead to a new understanding of mechanisms of motor neuron degeneration. It is reasonable to anticipate that our knowledge will eventually lead to further investigation on pharmacological methods for facilitating or protecting the reparative mechanism in motor neurons affected by motor neuron disease, such as ALS.