Interaction of α-synuclein with DJ-1 in homodimer and L166P mutant monomer forms in Parkinson's disease: a molecular dynamics study.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by the formation of Lewy bodies, which are primarily composed of misfolded α-Synuclein (α-Syn). DJ-1 is a crucial protein involved in the correct folding of α-Syn, and mutations impairing its function are associated with the onset of PD. One such mutation, the L166P substitution in DJ-1, which has been linked to early-onset PD and results in the loss of DJ-1's homodimer structure. Recent studies have shown the presence of DJ-1 in Lewy bodies, but its interaction with α-Syn is unknown. Therefore, in this study, we investigated the interaction between α-Syn and DJ-1 in both its wild-type (wDJ-1: homodimer) and L166P mutant (mDJ-1: monomer) forms using molecular dynamics simulation. Our results indicated that α-Syn binds more tightly to mDJ-1 than to wDJ-1. Gibbs free energy landscape analysis showed that the bonded α-Syn to mDJ-1 complex represents a stable conformation, whereas only a partial connection of α-Syn to wDJ-1 was observed. Generally, it appears that the monomer form of DJ-1 resulting from the L166P mutation can form a stable complex with α-Syn, potentially intensifying the formation of Lewy bodies. Thus, the identification of aggregated α-Syn with DJ-1 may serve as a potential biomarker for PD.