Utilizing Protein Structural Data to Understand The Basis of Neurodegenerative Diseases

The majority of neurodegenerative diseases are caused by protein misfolding. The general mechanism is of an initial misfolding event of tau and amyloid-ß and α-synuclein to a ß-sheet rich amyloid fibril seed. Subsequent rounds of templating and propagation of the amyloid fibril leads to the aggregate formation and cell death. Improved structural techniques have enabled the resolution of many amyloid structures, illustrating the diverse amyloid conformations a single protein can adopt, termed strains, with each structure having distinct biochemical and pathological properties evidenced in cellular, mouse, and cell-free studies. While many studies are investigating the process of templating among misfolded proteins, the question of how initial misfolding occurs and how that contributes to strain formation remains unclear. This study aims to survey structures of amyloid proteins deposited in the Protein Data Bank, an open-source repository for three-dimensional nucleic acid and protein structures and employ a Ramachandran-based analysis to investigate strain formation. The conservation of the dihedral angles phi and psi were analyzed across residues of amyloid structures. Initial analyses revealed the presence of multiple chain redirection/reversal motifs in the α-synuclein amino acid sequence, often forming at consistent residue locations. The presence of extrinsic and intrinsic factors including chain redirection/reversals, mutations/post-translational modifications, cofactor presence, and fibril sources were investigated to see how they correlated with dihedral angle variability. A hierarchy was made to determine which of the factors would have the greatest influence on strain formation, hypothesized as having the lowest dihedral angle variability.