Transgenic mice expressing a mutated human Cu/Zn superoxide dismutase (SOD1) gene develop a motor neuron disease similar to familial amyotrophic lateral sclerosis (FALS). While the histopathology and the inflammatory reactions in the spinal cord of these mice are well described, their spatiotemporal extension into brain areas and the relationship between degenerative and inflammatory events remain obscure. In the present study, we investigated the time course and extent of degenerative changes and inflammatory reactions in the CNS during progression of the disease in a transgenic FALS model, the SOD1-G93A mouse with histological and immunohistochemical methods. Compared to non-transgenic littermates, the SOD1-G93A transgenics developed widespread degeneration in both motor and extra-motor regions up to telencephalic regions, including the cerebral cortex but sparing distinct regions like the striatum and hippocampus. We provide evidence that these degenerative processes are accompanied by intense inflammatory reactions in the brain, which spatiotemporally correlate with degeneration and comprise besides strong astro- and microgliotic reactions also an influx of peripheral immune cells such as T-lymphocytes and dendritic cells. Both degeneration and inflammatory reactions spread caudocranially, starting at 2 months in the spinal cord and reaching the telencephalon at 5 months of age. Since the corticospinal tract lacked any signs of degeneration, we conclude that the upper and the lower motor neurons degenerate independently of each other.