Structure Specific Neuro-toxicity of α-Synuclein Oligomer

Abstract

Parkinson disease (PD) is linked to alpha-synuclein (aS) aggregation and deposition of amyloid in the substantia nigra region of the brain tissues. Recent reports suggested that oligomeric assembly structure could be neurotoxic to neuronal cells. In the current investigation we produced two distinct classes of aS oligomers and link the protein conformation state and stability to neuronal cell toxicity. Natural oligomers (NO) enriched with alpha-helical folds are produced in storage of aS at below -20°C for 7 days. Induced oligomer (IO), often observed in the aggregation pathway of aS were made incubating the protein solution at 37 °C. Natural oligomers remained stable and did not transform into beta-sheet rich amyloid fiber and exhibited higher toxicity (80% cell death) compared to induced oligomers. Natural oligomers were ovular shape and the size ranged between 4-5.5 nm. It maintained significant number (~ 60%) of residues in alpha-helical conformational space. However, initiation of hydrophobic zipping with beta sheet conformation was evidenced in induced oligomer (IO) and a lesser number residues (45%) remained with preference to alpha-helical secondary structure. Hydrophobic collapse leads the transformation of IO into thermodynamically most stable beta-sheet rich amyloid fibril. Molten globule like secondary structure stabilized by H-bonding in natural oligomers caused enhanced stability and cellular toxicity compared to induced oligomer. Thus off-pathway/natural oligomers could be plausible reason of neuronal cell death and possible cause of Parkinson disease.