Aggregation
of α-synuclein (α-Syn) into neurotoxic
oligomers and amyloid fibrils is suggested to be the pathogenic mechanism
for Parkinson’s disease (PD). Recent studies have indicated
that oligomeric species of α-Syn are more cytotoxic than their
mature fibrillar counterparts, which are responsible for dopaminergic
neuronal cell death in PD. Therefore, the effective therapeutic strategies
for tackling aggregation-associated diseases would be either to prevent
aggregation or to modulate the aggregation process to minimize the
formation of toxic oligomers during aggregation. In this work, we
showed that arginine-substituted α-Syn ligands, based on the
most aggregation-prone sequence of α-Syn, accelerate the protein
aggregation in a concentration-dependent manner. To elucidate the
mechanism by which Arg-substituted peptides could modulate α-Syn
aggregation kinetics, we performed surface plasmon resonance (SPR)
spectroscopy, nuclear magnetic resonance (NMR) studies, and all-atom
molecular dynamics (MD) simulation. The SPR analysis showed a high
binding potency of these peptides with α-Syn but one that was
nonspecific in nature. The two-dimensional NMR studies suggest that
a large stretch within the C-terminus of α-Syn displays a chemical
shift perturbation upon interacting with Arg-substituted peptides,
indicating C-terminal residues of α-Syn might be responsible
for this class of peptide binding. This is further supported by MD
simulation studies in which the Arg-substituted peptide showed the
strongest interaction with the C-terminus of α-Syn. Overall,
our results suggest that the binding of Arg-substituted ligands to
the highly acidic C-terminus of α-Syn leads to reduced charge
density and flexibility, resulting in accelerated aggregation kinetics.
This may be a potentially useful strategy while designing peptides,
which act as α-Syn aggregation modulators
