ABSTRACT
In Parkinson's disease patients, α-synuclein is the major component of the intracellular protein aggregates found in dopaminergic neurons. Previously, short synthetic α-synuclein-derived peptides have been shown to not only prevent α-synuclein fibrillation but also dissolve preformed α-synuclein aggregates in vitro. The hexapeptide PGVTAV was the shortest peptide that retained the ability to block α-synuclein fibrillation. For preventative or therapeutic effectiveness, a treatment must suppress the neurotoxicity of α-synuclein aggregates and remain stable in plasma. The present study shows that specific peptides can protect neuronal cells from α-synuclein aggregation-induced cell death. The ß-sheet-breaking hexapeptide PGVTAV remained intact in human plasma for longer than one day, suggesting that it may be a candidate for the development of therapeutics to treat Parkinson's disease.
Subject(s)
Antiparkinson Agents/chemistry , Antiparkinson Agents/pharmacology , Oligopeptides/chemistry , Oligopeptides/pharmacology , alpha-Synuclein/antagonists & inhibitors , Animals , Antiparkinson Agents/blood , Cell Line, Tumor , Humans , Mice , Oligopeptides/blood , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Protein Stability , Protein Structure, Secondary , alpha-Synuclein/metabolismABSTRACT
alpha-Synuclein is the major components of the intracellular protein-aggregates, found in the dopaminergic neurons of Parkinson's disease patients. Previously, we screened for alpha-synuclein substitution mutants that prevent fibril formation of both wild-type and Parkinson's disease-linked alpha-synuclein variants. In the present study, we show that short synthetic peptides derived from these mutant sequences not only prevented alpha-synuclein fibrillation but also dissolved preformed alpha-synuclein aggregates in vitro. The hexapeptide PGVTAV, which was the shortest peptide that retained the ability to block alpha-synuclein fibrillation, may serve as a lead compound for the development of therapeutics for Parkinson's disease.