Excessive accumulation of neurofilaments in the cell bodies and proximal axons of motor neurons is a major pathological hallmark during the early stages of many human motor neuron diseases. To test directly the consequence of overexpression of the major neurofilament subunit NF-L, we produced transgenic mice that accumulate NF-L to-4-fold the normal level in the sciatic nerve. In young animals, the motor neurons of the ventral horn of the spinal cord have massive accumulations of neurofllaments, swollen perlkarya, and eccentrically localized nuclei. NF-L accumulation is accompanied by an increased frequency of axonal degeneration, proximal axon swelling, and severe skeletal muscle atrophy. These data indicate that extenalve accumulation of neurofllaments in motor neurons can trigger the neurodegenerative process.