A Characterization of Misfolded Alpha‐Synuclein in Parkinson’s Disease

Abstract

The Moeller SMART Team in conjunction with Dr. JiaJie Diao at the University of Cincinnati Medical College and MSOE Center for Biomolecular Modeling used 3‐D modeling and printing technology to study the role of misfolded alpha‐synuclein proteins in Parkinson’s Disease (PD). Neurodegenerative diseases are all characterized by the aggregation of misfolded proteins that form an insoluble substrate. Misfolded alpha‐synuclein is thought to be the protein involved in PD. This protein is natively found as an unfolded monomer that can take on many different conformations. It consists of 140 amino acids and is divided into three regions: the N‐terminal region (residues 1–60), non‐amyloid beta component (NAC) (residues 61–95), and the C‐terminus (residues 96–140). Alpha‐synuclein shows the ability to form amyloid fibrils which are associated with toxicity. Subunits within the fibrils adopt a beta‐strand conformation with hydrogen bonding between adjacent beta strands to form long linear polymers. The N‐terminal and C‐terminal residues display a random coil arrangement that are not involved in hydrogen bonding. The central beta sheet core is comprised of an inner hydrophobic region that interlocks into compact right‐angled spirals. Each fibril can form a dimer with rotational symmetry about the bonding interface. Within the beta sheet region, the NAC and pre‐NAC regions are responsible for fibril formation. The NAC region is the central hydrophobic region that when removed from alpha‐synuclein leads to the inability of aggregation.