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

被引：23

作者：

Kumar, Roshan ^{[1
,2
]}

Kumar, Sanjay ^{[1
,2
]}

Hanpude, Pranita ^{[1
]}

Singh, Abhishek Kumar ^{[1
]}

Johari, Tanu ^{[1
,2
]}

Majumder, Sushanta ^{[1
]}

Maiti, Tushar Kanti ^{[1
]}

机构：

[1] NCR Biotech Sci Cluster, Reg Ctr Biotechnol, Funct Prote Lab, 3rd Milestone Gurgaon Faridabad Expressway, Faridabad 121001, India

[2] Manipal Acad Higher Educ, Manipal 576104, Karnataka, India

来源：

COMMUNICATIONS BIOLOGY | 2019年 / 2卷 / 1期

关键词：

DISEASE PROTEIN DJ-1; ALPHA-SYNUCLEIN; MOLECULAR CHAPERONE; CRYSTAL-STRUCTURE; MITOCHONDRIAL LOCALIZATION; SPORADIC PARKINSON; OXIDATIVE STRESS; BINDING; MECHANISM; LEADS;

D O I：

10.1038/s42003-019-0644-7

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

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

引用

页数：14

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