Cheruvara H, Allen-Baume VL, Kad NM, Mason JM.,Â J. Biol. Chem.,Â 2015, First published on-line: January 23, 2015. Â DOI:Â 10.1074/jbc.M114.620484
Aggregation of Î±-synuclein (Î±-syn) into toxic fibrils is a pathogenic hallmark of Parkinson’s disease (PD). Studies have largely focused on residues 71-82, yet most early onset mutations are located between residues 46-53. A semi-rationally designed 209,952 member library library based entirely on this region was constructed, containing all wild-type residues and changes associated with early onset PD. Intracellular cell-survival screening and growth competition isolated a 10-residue peptide antagonist that potently inhibits Î±-syn aggregation and associated toxicity at 1:1 stoichiometry. This was verified using continuous growth measurements, and MTT cytotoxicity studies. Atomic force microscopy, and circular dichroism on the same samples showed a random-coil structure and no oligomers. A new region of Î±-syn for inhibitor targeting has been highlighted, together with the approach of using semi-rational design and intracellular screening. These peptides are candidates for modification into drugs capable of slowing or even preventing the onset of PD.