Neurofilaments and Motor Neuron Disease

Abstract

Motor neuron disease is clinically characterized by progressive muscle wasting leading to total muscle paralysis. In the most prominent disease, amyotrophic lateral sclerosis, or ALS, a long history of pathological study has firmly established that the primary lesion site is in spinal and cortical motor neurons. Although widespread loss of these neurons is seen late in the pathogenic progression, the earliest detectable abnormalities are aberrant accumulations of neurofilaments in cell bodies and proximal axons. To test whether accumulation of neurofilaments directly contributes to the pathogenic process, transgenic mice that produce high levels of neurofilaments in motor neurons have been generated. These transgenic mice show most of the hallmarks observed in motor neuron disease, including swollen perikarya with eccentrically localized nuclei, proximal axonal swellings, axonal degeneration and severe skeletal muscle atrophy. These data indicate that excessive accumulation of neurofilaments can trigger selective motor neuron failure. Since such accumulation is seen both in sporadic and familial ALS, it is almost certain to be a key intermediate in the pathway of pathogenesis leading to neuronal loss.