Abstract
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.
Highlights
DJ-1 is a deglycase enzyme which exhibits a redox-sensitive chaperone-like activity
It has been demonstrated that DJ-1Pox shows chaperone function and inhibits the aggregation of α-synuclein. α-Synuclein aggregation inhibition by DJ-1 might work through inhibition of nucleation or fiber elongation processes or disassembly of fibers
DJ-1Pox and DJ-1Cox species have been made in in vitro condition based on the published protocol[24]
Summary
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. In addition to these established functions, molecular chaperones play an important role in solublization of amyloidogenic proteins in initial stages of the aggregation pathway by preventing self-assembly of disease associated proteins into toxic oligomers[2]. It is clear that molecular chaperones interact with monomeric, misfolded, or unfolded forms of proteins and with a variety of aggregated intermediates and restrict aggregation process at different stages including primary nucleation, secondary nucleation, fiber elongation and fragmentation of mature fibrils. There are many chaperones including small heat shock proteins, Hsp[70], and Hsp[104] that inhibit the monomeric or oligomeric state of α-synuclein and prevent fibrillation in vivo and in vitro[6,7,8]. The oxidation of Cys[106] to the sulfinate state has neuroprotective functions[25]
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