INVOLVEMENT OF NEUROFILAMENTS IN MOTOR-NEURON DISEASE

Motor neuron disease is clinically characterized by progressive muscle wasting leading to total muscle paralysis. A long history of patholog ical study of patients has firmly established that the primary lesion site is in spinal and cortical motor neurons. In addition to the wides pread loss of these neurons, neuronal abnormalities including massive accumulation of neurofilaments in cell bodies and proximal axons have been also widely observed, particularly in the early stages of the dis ease. To test whether high accumulation of neurofilaments directly con tributes to the pathogenic process, transgenic mice that produce high levels of neurofilaments in motor neurons have been generated. These t ransgenic mice show most of the hallmarks observed in motor neuron dis ease, including swollen perikarya with eccentrically localized nuclei, proximal axonal swellings, axonal degeneration and severe skeletal mu scle atrophy. These data indicate that extensive accumulation of neuro filaments in motor neurons can trigger a neurodegenerative process and may be a key intermediate in the pathway of pathogenesis leading to n euronal loss.