Interaction of Α-Synuclein With Dj-1 in Homodimer and L166p Mutant Monomer Forms in Parkinson’S Disease: A Molecular Dynamics Study Publisher



Alipour M¹ ; Hajipourverdom B^{2, 3} ; Zali A¹ ; Ashrafi F¹ ; Abdolmaleki P³ ; Oraeeyazdani S¹ ; Akhlaghdoust M^{1, 4} ; Karimi N⁵ Show Affiliations
Source: Journal of Biomolecular Structure and Dynamics Published:2025

Abstract

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. © 2025 Informa UK Limited, trading as Taylor & Francis Group.