Neuroinflammatory aberrations of arachidonate pathway in ALS
Kenneth Hensley, Ph.D.
Amyotrophic lateral sclerosis (ALS) is caused by the death of motor neurons. Recent data suggests that neurons don’t die, so much as they are killed by surrounding cells called glia. The glia usually support and nourish neurons but they can become dysfunctional and toxic in certain diseases. This process is called “neuroinflammation”. Cytokines are small proteins used to communicate between neurons, astrocytes (one of the major types of glia) and microglia (a second type of glial cell). Recent data suggests that neuroinflammation in a mouse model of ALS is caused by dysregulated cytokine signaling. The cytokine signaling is, in turn, regulated by major lipid metabolic pathways. The lipid arachidonic acid is converted to prostaglandins by the enzyme COX-II, or leukotrienes by the enzyme 5LOX. We have found that prostaglandins and leukotrienes are elevated in the ALS mouse, and that these molecules hypersensitize glia. The proposed research intends to genetically ablate either 5LOX from ALS mice in order to confirm (or disprove) involvement of this enzyme in the disease process. A second goal of the research is to test the ability of a 5LOX inhibitor to slow disease progression in the ALS mouse, and to continue the development of more potent anti-neuroinflammatory compounds that function partly by antagonizing 5LOX.
