An α-synuclein decoy peptide prevents cytotoxic α-synuclein aggregation caused by fatty acid binding protein 3

alpha-synuclein (alpha Syn) is a protein known to form intracellular aggregates during the manifestation of Parkinson's disease. Previously, it was shown that aSyn aggregation was strongly suppressed in the midbrain region of mice that did not possess the gene encoding the lipid transport protein fatty acid binding protein 3 (FABP3). An interaction between these two proteins was detected in vitro, suggesting that FABP3 may play a role in the aggregation and deposition of aSyn in neurons. To characterize the molecular mechanisms that underlie the interactions between FABP3 and aSyn that modulate the cellular accumulation of the latter, in this report, we used in vitro fluorescence assays combined with fluorescence microscopy, transmission electron microscopy, and quartz crystal microbalance assays to characterize in detail the process and consequences of FABP3-alpha Syn interaction. We demonstrated that binding of FABP3 to aSyn results in changes in the aggregation mechanism of the latter; specifically, a suppression of fibrillar forms of alpha Syn and also the production of aggregates with an enhanced cytotoxicity toward mice neuro2A cells. Because this interaction involved the C-terminal sequence region of alpha Syn, we tested a peptide derived from this region of alpha Syn (alpha SynP130-140) as a decoy to prevent the FABP3-alpha Syn interaction. We observed that the peptide competitively inhibited binding of alpha Syn to FABP3 in vitro and in cultured cells. We propose that administration of alpha SynP130-140 might be used to prevent the accumulation of toxic FABP3-alpha Syn oligomers in cells, thereby preventing the progression of Parkinson's disease.