Gene Expression in Motor Neurons with Differential Susceptibility to ALS

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Motor neuron death is a major feature of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease that leads to paralysis and death. Although most motor neurons die in ALS, some populations are resistant to degeneration. This exploratory proposal is designed to compare gene expression in motor neurons that are resistant to ALS with those that are vulnerable to ALS. The long term objectives of these experiments are to identify genes that confer protection to certain motor neurons and, ultimately, to induce expression of these genes in motor neurons that typically succumb to ALS. To accomplish these goals, we will compare gene expression in the bulbocavernosus and oculomotor nuclei, motor neuron populations that are resistant to ALS, with gene expression in the retrodorsolateral and trigeminal nuclei, motor neuron populations that are vulnerable to ALS, in both wildtype and ALS transgenic rats. The following aims will be investigated: Specific Aim 1: Compare gene expression in populations of motor neurons with differential susceptibility to ALS. These experiments will use gene microarray analysis of motor neurons after laser capture microdissection and RNA amplification. Specific Aim 2: Examine expression of specific genes identified in motor neurons with differential susceptibility to ALS. These experiments will use RT-PCR, in situ hybridization and immunohistochemistry. Specific Aim 3: Determine whether molecules associated with ALS- resistant motor neurons are differentially affected in a transgenic rat model of ALS. These experiments will use the techniques of Specific Aim 2 in transgenic SOD-1 mutant rats. Death of motor neurons is a hallmark of ALS, a paralyzing neurological disease that is fatal. Understanding how some motor neuron populations resist degeneration, even in late stage disease, may provide clues about targets for gene therapy in motor neurons at risk for degeneration in ALS.