Grant: Doctoral Research Award - Priority Announcement: Amyotrophic Lateral Sclerosis

ALS is a disease of the central nervous system that typically develops later in life, and usually results in degeneration of nerve cells (or neurons), muscle paralysis, and eventually death. A major factor that has been implicated in ALS is highly elevated tumor necrosis factor alpha (TNFa), which is a protein that is released by the supporting cells of the brain - glia. However, the mechanism through which TNFa leads to nerve cell degeneration is not clearly understood. Recently, a link was discovered between TNFa and glutamate receptors which normally mediate neuron-to-neuron communication; specifically a subset of those glutamate receptors composed of the protein GluR1 can cause excessive calcium influx leading to cell death, and TNFa was found to specifically increase the GluR1. It is our aim to investigate, using a mouse genetic model of ALS called SOD1G93A, whether increased TNFa release from glia can result in an increase in GluR1 on the surface of neurons. This will be carried by measuring GluR1 levels on the surface of neurons grown in culture, and exposed to glia isolated from SOD1G93A mice, compared to neurons exposed to glia from normal mice. From there, we will proceed to study the molecular mechanism that TNFa uses to induce the increase in surface GluR1 levels on neurons. This will be carried out using inhibitor compounds that can target one of the several signalling molecules that are known to be activated by TNFa. The objective would be to identify a specific signalling molecule, or a subset of signalling molecules downstream of TNFa that mediate the increase in GluR1 levels, so that we may be able to manipulate those molecule(s) experimentally, and therapeutically.