Research

Amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease) is a dreaded incurable neurodegenerative disease of unknown cause. It results in progressive paralysis, muscle atrophy, and death, usually from respiratory complications. Our team studies two complementary lines of research.

Molecular mechanisms of motor neuron degeneration: We use the spontaneous mutant wobbler mouse and transgenic mouse overexpressing the G93 mutant human Cu,Zn-superoxide dismutase (SOD1G93A) gene. We test therapies to prevent neurodegeneration and rescue the phenotype.

Magnetic resonance imaging (MRI) to identify motor pathway abnormalities: We study brains of ALS patients and mouse models for post mortem histopathologic correlation. As in ALS, protein breakdown is abnormal in wobbler mouse spinal cord and brain, resulting in intraneuronal accumulation of potentially damaging protein inclusions. By finding which proteins accumulate and the causal mechanisms, we hope for insights into mechanisms of ALS neurodegeneration applicable to novel treatments. With Richard Ransohoff, M.D., we found that activation of microglia in SOD1G93A ALS mice results in increased motor neuron death and faster disease progression. We are characterizing gene pathways involved in microglia-mediated neuronal death to find new ways to block it, slowing ALS progression. We have retarded disease progression in wobbler mice by incorporating a gene mutation (slow Wallerian degeneration, Wlds) known to delay axonal degeneration.

We study the mechanism of this neuroprotection and plan to use viral delivery of the Wlds gene into diseased mice to delay disease progression.