Slow component of axonal transport is impaired in the proximal axon of transgenic mice with a G93A mutant SOD1 gene

The purpose of this study was to determine whether slow axonal transport of neurofilaments (NFs) is impaired in the spinal cord of G93A Cu/Zn superoxide dismutase (SOD1) mutant transgenic mice expressing a relatively low mutant protein (gene copy 10) and, if so, how the impairment occurs in this animal model. Transgenic mice were killed at the ages of 24, 28 and 32 weeks, and the cervical and lumbar spinal cords were examined under an electron microscope. Age-matched non-transgenic wild-type mice served as controls. At 24 weeks (early presymptomatic stage), anterior horn cells were well preserved. The earliest morphological changes were mild vacuolar changes in the neuronal processes, particularly in proximal axons. At 28 weeks (late presymptomatic stage), mild neuronal loss of anterior horn neurons was observed. Vacuolar changes were more prominent in the proximal axons, including swollen axons (spheroids) and neuropils of the anterior horns. Vacuoles in the axons were frequently large enough to occupy almost the entire axonal caliber. The anterior roots were degenerative, showing vacuolar changes and myelin ovoids. Lewy body-like inclusions (LIs) consisting of filaments thicker than NFs (about 1.5 times larger in diameter) were frequently demonstrated in the neuronal processes including swollen axons (spheroids) and occasionally in the somata. At 32 weeks (symptomatic stage), the anterior horns showed a moderate to severe neuronal loss accompanied by prominent astrogliosis. Cord-like swollen axons consisting of accumulated NFs and many neurofilamentous accumulations were frequently observed in the anterior horn. Vacuolar changes were less prominent or disappeared in the neuropils of the anterior horns and the anterior roots, whereas LIs were frequently demonstrated within the neuronal processes including the cord-like swollen axons. In the anterior roots, degenerative changes such as marked fiber loss and frequent myelin ovoids were remarkable. No accumulation of NFs or mitochondrial vacuolation was detected in somata or proximal dendrites at any stage. These findings suggest that the slow component of axonal transport in the proximal axons is impaired at an early stage in this transgenic mouse model, and that the impairment is probably caused by a mechanical impediment of NFs, or by the accumulation of NFs in the proximal axon, as a result of the obstruction of the axonal flow that initially occurs by vacuolar changes, and is later exacerbated by accumulation of LIs.