Partially oxidized DJ-1 inhibits α-synuclein nucleation and remodels mature α-synuclein fibrils in vitro

摘要

DJ-1 is a deglycase enzyme which exhibits a redox-sensitive chaperone-like activity. The partially oxidized state of DJ-1 is active in inhibiting the aggregation of α-synuclein, a key protein associated with Parkinson’s disease. The underlying molecular mechanism behind α-synuclein aggregation inhibition remains unknown. Here we report that the partially oxidized DJ-1 possesses an adhesive surface which sequesters α-synuclein monomers and blocks the early stages of α-synuclein aggregation and also restricts the elongation of α-synuclein fibrils. DJ-1 remodels mature α-synuclein fibrils into heterogeneous toxic oligomeric species. The remodeled fibers show loose surface topology due to a decrease in elastic modulus and disrupt membrane architecture, internalize easily and induce aberrant nitric oxide release. Our results provide a mechanism by which partially oxidized DJ-1 counteracts α-synuclein aggregation at initial stages of aggregation and provide evidence of a deleterious effect of remodeled α-synuclein species generated by partially oxidized DJ-1. Kumar et al investigate how the partially oxidized state of protein DJ-1 (DJ-1Pox) inhibits aggregation of α-synuclein, a hallmark of Parkinson’s disease. They find that DJ-1Pox show enhanced adhesive properties, sequesters α-synuclein monomers to prevent nucleation and remodels α-synuclein fibrils in vitro.