Enhanced superoxide dismutase-2 immunoreactivity of astrocytes and occasional neurons in amyotrophic lateral sclerosis

The recent discovery of missense mutations in the superoxide dismutase (SOD)-1 gene as a cause of familial amyotrophic lateral sclerosis (ALS) and the ensuing description of transgenic SOD-1 mutant mouse models have focussed scientific interest on free radical scavenging mechanisms in all other familial (FALS) and sporadic (SALS) forms of the disease. We have compared the presence of intracellular cytosolic copper-zinc SOD-1 and mitochondrial manganese SOD-2 in the CNS from FALS and SALS patients and from non-neurological controls by immunohistochemical assessment, in the knowledge that no SOD-1 mutations have been found in any of 18 Dutch ALS pedigrees. ALS specimens from the motor cortex and the spinal cord presented enhanced SOD-2 immunoreactivity, especially of astrocytes and occasionally of neurons. Astrocyte staining appeared to be increased at the cerebral cortical and the spinal cervical and lumbar levels, but was only slightly increased in the thoracic anterior horns and not at all in the brain stem. This indicates that, by the time of death, the disease had burnt out in the brain stem and thoracic cord. Increased staining of neurons was limited to the small lateral and dorsal nuclei of the spinal cord. FALS and SALS cases exhibited the same staining patterns. SOD-1 immunoreactivity did not differ between disease and control specimens. SOD-1 and -2 staining was normal in the ALS cortical, brain stem and spinal motoneurons. This suggests that SALS and non-SOD-1 mutant FALS are not accompanied by loss of SOD-1 or -2 protein. An enzyme-linked immunosorbent assay revealed no differences in SOD-1 and SOD-2 levels between ALS patients and controls. Our major finding of locally increased SOD-2 immunoreactivity of astrocytes in FALS and SALS specimens, probably reflects reactive fibrillary and protoplasmatic gliosis in areas of ongoing degeneration but may also result from an attempt at compensation for free radical injury.