Collections > Electronic Theses and Dissertations > The Mechanism of Cu,Zn Superoxide Dismutase Aggregation in Familial Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a degenerative disease of the motor neurons characterized by the progressive loss of muscle strength and eventual death due to selective killing of motor neurons in the brain stem and spinal cord. ALS consists of both sporadic and familial subtypes that share the same clinical progression of symptoms. Of the 10% of ALS cases considered familial ALS (FALS), 1 in 5 is the result of a mutation in the enzyme Cu,Zn superoxide dismutase (SOD1). Over 100 mutations have been identified, and though they are distributed evenly throughout the homodimeric structure of SOD1, the mutations have the general property of inducing SOD1 aggregation and toxicity in motor neurons and surrounding glial cells. In recent years, a shift has occurred in ALS research and the broader field of protein aggregation diseases toward the hypothesis that soluble oligomers, rather than the end products of aggregation, are the species responsible for the patterns of toxicity observed in these diseases. Previous studies of SOD1 oligomerization have thus far focused on large-scale oligomers and ignored the earliest stages of oligomerization during which the transition from the native state of SOD1 occurs. Knowledge of structural transformations that initiate SOD1 aggregation, as well as the structure of early oligomeric intermediates, is essential for the design of strategies to prevent the aggregation of SOD1 in FALS. The following chapters contain a multifaceted description of the initiation of SOD1 oligomerization including "first-principles" computational approaches for modeling the formation of aberrant SOD1 dimers, in vitro mechanistic studies of SOD1 oligomerization, as well as the characterization of the in vivo modification state of SOD1. By calling attention to the fact that SOD1 is highly post-translationally modified in-vivo and showing that mutations allow SOD1 to access altogether different oligomeric intermediates than wild type, we lay the groundwork for significant advances in understanding the structural basis of SOD1 oligomerization in ALS.