ALS-Linked SOD1 Mutant G85R Mediates Damage to Astrocytes and Promotes Rapidly Progressive Disease with SOD1-Containing Inclusions

TLDR

Familial ALS‑linked SOD1 mutants G93A and G37R have been shown to cause disease in mice via an acquired toxic property. Low levels of the G85R SOD1 mutant induce an extremely rapid motor neuron disease in mice, marked by SOD1‑positive astrocytic inclusions, ubiquitin‑positive motor neuron aggregates, a progressive loss of the glial glutamate transporter GLT‑1, and direct astrocyte damage that likely drives synchronous motor neuron degeneration.

Abstract

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.