Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes degeneration of motor neurons, leading to skeletal muscle atrophy, paralysis and death. Mutations in Cu/Zn superoxide dismutase (SOD1) are one cause of ALS. Transgenic mice that express mutated SOD1 develop ALS similar to human disease. To determine the mechanism by which mutant SOD1 causes motor neuron degeneration, we will test three hypothesis: 1) ALS caused by different SOD1 mutations undergo different clinical and pathological progression; 2) mitochondrial damage precedes the onset of muscle weakness and accumulation of this damage leads to a dysfunction and deletion of normal mitochondria in motor neurons, culminating the onset of ALS; 3) oxidative stress plays a role in triggering the onset of ALS. To test the first hypothesis, we will investigate the pathological evolution in correlation with clinical progression in mice expressing G85R mutation and compare the findings with G37R and G93A mutants. We will delineate and compare the sequence of pathological events leading to motor neuron death in these three lines. By this approach, we will determine the differences and common characteristics of ALS caused by different SOD1 mutations. The outcome of this study will provide guidance to further elucidation of the disease mechanism and help to improve prognosis and design therapies tailored to different mutations. To test the second hypothesis, we will use electron microscopy to characterize the types of mitochondrial abnormality before and after onset of the disease. We will also determine the earliest time when mitochondrial abnormalities emerge and quantify the changes in the number of normal and abnormal mitochondria before and after the onset of the disease. To test the role of mitochondrial abnormality in triggering the onset of the disease, we will test whether energy supplementation by administering creatine delays the onset of the disease. To test the third hypothesis, we will measure the levels of oxidative markers at different disease stages to determine whether oxidative damage precedes or follows the onset of ALS. Further, we will test whether and how anti-oxidant treatment changes the course of disease progression.
