Rats Expressing Human Cytosolic Copper–Zinc Superoxide Dismutase Transgenes with Amyotrophic Lateral Sclerosis: Associated Mutations Develop Motor Neuron Disease

TLDR

Familial ALS can be caused by mutations in the cytosolic copper–zinc superoxide dismutase (SOD1) gene. The study reports that rats expressing human SOD1 transgenes carrying ALS‑associated G93A or H46R mutations develop motor neuron degeneration and paralysis. The larger rat model permits spinal fluid and spinal cord manipulations, such as intrathecal catheter implantation and direct viral or cell therapy delivery, to facilitate chronic therapeutic studies. Rats with human SOD1 G93A or H46R mutations show selective spinal cord motor neuron loss, activation of apoptotic genes, and paralysis, underscoring the neurotoxic properties of mutant SOD1 in ALS.

Abstract

Some cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding cytosolic, copper–zinc superoxide dismutase (<i>SOD1</i>). We report here that rats that express a human <i>SOD1</i> transgene with two different ALS-associated mutations (G93A and H46R) develop striking motor neuron degeneration and paralysis. As in the human disease and transgenic ALS mice, pathological analysis demonstrates selective loss of motor neurons in the spinal cords of these transgenic rats. In spinal cord tissues, this is accompanied by activation of apoptotic genes known to be activated by mutant SOD1 protein <i>in vitro</i> and<i>in vivo</i>. These animals provide additional support for the proposition that motor neuron death in SOD1-related ALS reflects one or more acquired, neurotoxic properties of the mutant SOD1 protein. The larger size of this rat model as compared with the ALS mice will facilitate studies involving manipulations of spinal fluid (implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) and spinal cord (e.g., direct administration of viral- and cell-mediated therapies).