Morphological aspects of superoxide dismutase-1 mutation in amyotrophic lateral sclerosis and its transgenic mouse model

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative dise ase that primarily involves the motor neuron system. Recent investigations have obtained evidence that mutations in the gene for superoxide dismutase- 1 (SOD1) are detected in a subset of familiar ALS patients, and that mutant SOD1-expressing transgenic mice develop ALS-like clinicopathological featu res. Several in vitro studies suggest that SOD1-mutated ALS is caused by a newly acquired neurotoxicity of mutant SOD1, but not by reduced enzyme acti vity. From the viewpoint of morphology, we analyzed the immunolocalization of SOD1 and some other substances in spinal cords from familial ALS patient s with SOD1 Ala(4)-->Val mutation. The spinal cords of the ALS patients dem onstrated the characteristic neuronal hyaline inclusions (NHIs) immunoreact ive with antibodies to ubiquitin and phosphorylated neurofilament protein ( NFP) in the lower motor neurons and cordlike swollen axons. The NHIs contai ned the epitopes of SOD1 and N-epsilon-carboxymethyllysine (CML), one of th e major advanced glycation endproducts (AGE), whereas there was no focal ac cumulation of SOD1 and CML in control individuals. Immunoelectron microscop y depicted the SOD1 and CML determinants on the granule-associated thick li near structures that mainly compose the NHIs. We also performed a similar s tudy on mice carrying a transgene far Gly(93)-->Ala mutant SOD1. The spinal cords of the transgenic mice were characterized by the appearance of NHIs resembling those of familiar ALS and by vacuolar degeneration. The mouse NH Is were immunoreactive for ubiquitin, phophorylated NFP, SOD1 and CML. Our findings of the coexistence of SOD1 and AGE in both the human and mouse NHI s indicate that certain substances are implicated in glycoxidation in the p resence of oxidative stress originating from mutant SOD1 and finally deposi ted in the NHIs, suggesting a pathogenic role of the oxidative processes in motor neuron degeneration in vivo.