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

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 ?-synuclein, a key protein associated with Parkinson's disease. The underlying molecular mechanism behind ?-synuclein aggregation inhibition remains unknown. Here we report that the partially oxidized DJ-1 possesses an adhesive surface which sequesters ?-synuclein monomers and blocks the early stages of ?-synuclein aggregation and also restricts the elongation of ?-synuclein fibrils. DJ-1 remodels mature ?-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 ?-synuclein aggregation at initial stages of aggregation and provide evidence of a deleterious effect of remodeled ?-synuclein species generated by partially oxidized DJ-1.

SUBMITTER: Kumar R 

PROVIDER: S-EPMC6821844 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Kumar Roshan R   Kumar Sanjay S   Hanpude Pranita P   Singh Abhishek Kumar AK   Johari Tanu T   Majumder Sushanta S   Maiti Tushar Kanti TK  

Communications biology 20191030

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 al  ...[more]

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