Diseases of motor neurons are important causes of human morbidity and mortality, but their basic pathological processes are not well understood because of a paucity of animal models and a lack of methods adequate to answer specific questions regarding pathogeneses of these diseases. Recently, several excellent models have become available and strategies have been developed which will allow substantial progress in the future. Our objectives are to understand some of the mechanisms by which motor neurons are affected by or respond to disease including: axotomy (eg. regeneration); tetanus, botulinum and diptheria toxins; a variety of toxins causing neuropathies (acrylamide, IDPN and 2,5-hexanedione); and a new animal model of motor neuron disease -hereditary canine spinal muscular atrophy (HCSMA) - which shows pathologic features in common with amyotrophic lateral sclerosis (ALS). In ALS, HCSMA and IDPN intoxication, neurofilaments accumulate in and distend proximal axons. The pathogenesis of these axonal swellings and the ensuing neuronal destruction is not understood. It is likely that the axonal pathology reflects abnormalities in the axonal transport of proteins. Ultrastructural, autoradiographic, radiometric and biochemical methods provide approaches which can be used to analyze this hypothesis. Since HCSMA and IDPN intoxication reproduce the pathology of human disease, these models afford unique opportunities to characterize the temporal and spatial evolution of the pathologic changes and to investigate the mechanisms causing these abnormalities. These studies of diseases of motor neurons should provide significant new information concerning the mechanisms leading to chronic neurological disease in man.