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

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by the loss of upper and lower motor neurons in the brain and spinal cord. Onset occurs between 45 and 60 years with a quick disease progression. At present, there is no cure. Familial ALS accounts for approximately 10 % of all cases, of which 15 % are caused by mutations in copper-zinc superoxide dismutase 1 (SOD1). Mutations of SOD1 cause the protein to gain a toxic function, which causes disease. Mitochondria have been implicated early on in disease course. A pool of mutant SOD1 has been shown to be misfolded and associated with the mitochondria outer membrane. It is my hypothesis that association of the misfolded SOD1 with the outer mitochondria membrane causes pathology by altering mitochondrial function. My first objective is to cause the misfolding of wild-type SOD1 (SOD1WT) by inducing oxidative stress in mouse neurblastoma cells, as has been done previously. Following this, I will determine whether this misfolded SOD1WT is associated with mitochondria and then examine mitochondrial function. My second objective is to determine if and when mutant SOD1 association to mitochondria impairsfunction in isolated spinal cord mitochondria from SOD1 transgenic mice expressing an ALS causing mutations.