MOTOR NEURON DEGENERATION MUTANT

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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.