Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal, incurable neurodegenerative disease described by progressive degeneration of motor neurons. The most common familial form of ALS (fALS) has been associated with mutations in the Cu/Zn superoxide dismutase (SOD1) gene. Mutation-induced misfolding and aggregation of SOD1 is often found in ALS patients. In this work, we probe the aggregation properties of peptides derived from the SOD1. To examine the source of SOD1 aggregation, we have employed a computational algorithm to identify four peptides from the SOD1 protein sequence that aggregates into a fibril. Aided by computational algorithms, we identified four peptides likely involved in SOD1 fibrillization. These four aggregation-prone peptides were (14)VQGIINFE21, (30)KVWGSIKGL38, (DSVISLS107)-D-101, and (147)GVIGIAQ(153). In addition, the formation of fibril propensities from the identified peptides was investigated through different biophysical techniques. The atomic structures of two fibril-forming peptides from the C-terminal SOD1 showed that the steric zippers formed by (DSVISLS107)-D-101 and (147)GVIGIAQ(153) vary in their arrangement. We also discovered that fALS mutations in the peptide (147)GVIGIAQ(153) increased the fibril-forming propensity and altered the steric zipper's packing. Thus, our results suggested that the C-terminal peptides of SOD1 have a central role in amyloid formation and might be involved in forming the structural core of SOD1 aggregation observed in vivo.