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PMID:21320589

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Citation

Meloni, G and Vašák, M (2011) Redox activity of α-synuclein-Cu is silenced by Zn₇-metallothionein-3. Free Radic. Biol. Med. 50:1471-9

Abstract

The aggregation of α-synuclein (α-Syn), the major component of intracellular Lewy body inclusions in dopaminergic neurons of the substantia nigra, plays a critical role in the etiology of Parkinson disease (PD). Long-term effects of redox-active transition metals (Cu, Fe) and oxidative chemical imbalance underlie the disease progression and neuronal death. In this work, we provide evidence that a brain metalloprotein, Zn₇-metallothionein-3 (Zn₇MT-3), possesses a dynamic role in controlling aberrant protein-copper interactions in PD. We examined the properties of the α-Syn-Cu(II) complex with regard to molecular oxygen, the biological reducing agent ascorbate, and the neurotransmitter dopamine. The results revealed that under aerobic conditions α-Syn-Cu(II) possesses catalytic oxidase activity. The observed metal-centered redox chemistry significantly promotes the production of hydroxyl radicals and α-Syn oxidation and oligomerization, processes considered critical for cellular toxicity. Moreover, we show that Zn₇MT-3, through Cu(II) removal from the α-Syn-Cu(II) complex, efficiently prevents its deleterious redox activity. We demonstrate that the Cu(II) reduction by thiolate ligands of Zn₇MT-3 and the formation of Cu(I)₄Zn₄MT-3, in which an unusual oxygen-stable Cu(I)₄-thiolate cluster is present, comprise the underlying molecular mechanism by which α-Syn and dopamine oxidation, α-Syn oligomerization, and ROS production are abolished. These studies provide new insights into the bioinorganic chemistry of PD.

Links

PubMed Online version:10.1016/j.freeradbiomed.2011.02.003

Keywords

Animals; Cells, Cultured; Copper/chemistry; Copper/metabolism; Disease Models, Animal; Disease Progression; Dopamine/metabolism; Homeostasis; Humans; Male; Metallothionein/chemistry; Metallothionein/metabolism; Neurons/metabolism; Neurons/pathology; Oxidation-Reduction; Parkinson Disease/metabolism; Parkinson Disease/pathology; Parkinson Disease/physiopathology; Rats; Substantia Nigra/pathology; alpha-Synuclein/genetics; alpha-Synuclein/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:MT3

enables

GO:0008270: zinc ion binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:MT3

enables

GO:0005507: copper ion binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:MT3

involved_in

GO:0051354: negative regulation of oxidoreductase activity

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P37840)

Seeded From UniProt

complete

HUMAN:MT3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P37840

F

Seeded From UniProt

complete

HUMAN:SYUA

enables

GO:0016491: oxidoreductase activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(CHEBI:18243)

Seeded From UniProt

complete

HUMAN:SYUA

involved_in

GO:0031648: protein destabilization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SYUA

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P25713

F

Seeded From UniProt

complete

HUMAN:SYUA

involved_in

GO:0031648: protein destabilization

ECO:0000314: direct assay evidence used in manual assertion

P

happens_during:(GO:0071280)

Seeded From UniProt

complete

HUMAN:SYUA

enables

GO:0016491: oxidoreductase activity

ECO:0000314: direct assay evidence used in manual assertion

F

has_direct_input:(CHEBI:18243)

Seeded From UniProt

complete

HUMAN:SYUA

involved_in

GO:0055114: oxidation-reduction process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SYUA

involved_in

GO:0071280: cellular response to copper ion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SYUA

enables

GO:0005507: copper ion binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:SYUA

involved_in

GO:0071872: cellular response to epinephrine stimulus

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SYUA

involved_in

GO:0051583: dopamine uptake involved in synaptic transmission

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SYUA

involved_in

GO:0097435: supramolecular fiber organization

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SYUA

involved_in

GO:0042416: dopamine biosynthetic process

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SYUA

involved_in

GO:0014059: regulation of dopamine secretion

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

See also

References

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