High levels of familial Amyotrophic Lateral Sclerosis (ALS)-linked SOD1 mutants G93A and G37R were previously shown to mediate disease in mice through an acquired toxic property. We report here that even low levels of another mutant, G85R, cause motor neuron disease characterized by an extremely rapid clinical progression, without changes in SOD1 activity. Initial indicators of disease are astrocytic inclusions that stain intensely with SOD1 antibodies and ubiquitin and SOD1-containing aggregates in motor neurons, features common with some cases of SOD1 mutant-mediated ALS. Astrocytic inclusions escalate markedly as disease progresses, concomitant with a decrease in the glial glutamate transporter (GLT-1). Thus, the G85R SOD1 mutant mediates direct damage to astrocytes, which may promote the nearly synchronous degeneration of motor neurons.
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We thank Ms. Marilyn Peper for her assistance with immunocytochemical preparations. This work has been supported by grants from the NIH (NS 27036 to Dr. Cleveland and AG 05146 to Dr. Price) and the Amyotrophic Lateral Sclerosis Association (to Drs. Cleveland, Borchelt, and Lee). Dr. Bruijn receives support as a Postdoctoral Fellow of the Muscular Dystrophy Association. Dr. Price is the recipient of a Leadership and Excellence in Alzheimer's Disease (LEAD) Award from NINDS (NS 10580).