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Differential effects of Cu2+ and Fe3+ ions on in vitro amyloid formation of biologically-relevant ?-synuclein variants.

ABSTRACT: Alterations in metal ion homeostasis appear coupled to neurodegenerative disorders but mechanisms are unknown. Amyloid formation of the protein ?-synuclein in brain cells is a hallmark of Parkinson's disease. ?-Synuclein can bind several metal ions in vitro and such interactions may affect the assembly process. Here we used biophysical methods to study the effects of micromolar concentrations of Cu2+ and Fe3+ ions on amyloid formation of selected ?-synuclein variants (wild-type and A53T ?-synuclein, in normal and N-terminally acetylated forms). As shown previously, Cu2+ speeds up aggregation of normal wild-type ?-synuclein, but not the acetylated form. However, Cu2+ has a minimal effect on (the faster) aggregation of normal A53T ?-synuclein, despite that Cu2+ binds to this variant. Like Cu2+, Fe3+ speeds up aggregation of non-acetylated wild-type ?-synuclein, but with acetylation, Fe3+ instead slows down aggregation. In contrast, for A53T ?-synuclein, regardless of acetylation, Fe3+ slows down aggregation with the effect being most dramatic for acetylated A53T ?-synuclein. The results presented here suggest a correlation between metal-ion modulation effect and intrinsic aggregation speed of the various ?-synuclein variants.

SUBMITTER: Lorentzon E

PROVIDER: S-EPMC7295844 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Differential effects of Cu2+ and Fe3+ ions on in vitro amyloid formation of biologically-relevant α-synuclein variants.

Lorentzon Emma E Kumar Ranjeet R Horvath Istvan I Wittung-Stafshede Pernilla P

Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 20200313 2-3

Alterations in metal ion homeostasis appear coupled to neurodegenerative disorders but mechanisms are unknown. Amyloid formation of the protein α-synuclein in brain cells is a hallmark of Parkinson's disease. α-Synuclein can bind several metal ions in vitro and such interactions may affect the assembly process. Here we used biophysical methods to study the effects of micromolar concentrations of Cu2+ and Fe3+ ions on amyloid formation of selected α-synuclein variants (wild- ...[more]

PMID: 32170541

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Project description:Copper binding to α-synuclein (α-Syn), the major component of intracellular Lewy body inclusions in substantia nigra dopaminergic neurons, potentiate its toxic redox-reactivity and plays a detrimental role in the etiology of Parkinson disease (PD). Soluble α-synuclein-Cu(II) complexes possess dopamine oxidase activity and catalyze ROS production in the presence of biological reducing agents via Cu(II)/Cu(I) redox cycling. These metal-centered redox reactivities harmfully promote the oxidation and oligomerization of α-Syn. While this chemistry has been investigated on recombinantly expressed soluble α-Syn, in vivo, α-Syn is acetylated at its N-terminus and is present in equilibrium between soluble and membrane-bound forms. This post-translational modification and membrane-binding alter the Cu(II) coordination environment and binding modes and are expected to affect the α-Syn-Cu(II) reactivity. In this work, we first investigated the reactivity of acetylated and membrane-bound complexes, and subsequently addressed whether the brain metalloprotein Zn7-metallothionein-3 (Zn7MT-3) possesses a multifaceted-role in targeting these aberrant copper interactions and consequent reactivity. Through biochemical characterization of the reactivity of the non-acetylated/N-terminally acetylated soluble or membrane-bound α-Syn-Cu(II) complexes towards dopamine, oxygen, and ascorbate, we reveal that membrane insertion dramatically exacerbates the catechol oxidase-like reactivity of α-Syn-Cu(II) as a result of a change in the Cu(II) coordination environment, thereby potentiating its toxicity. Moreover, we show that Zn7MT-3 can efficiently target all α-Syn-Cu(II) complexes through Cu(II) removal, preventing their deleterious redox activities. We demonstrate that the Cu(II) reduction by the thiolate ligands of Zn7MT-3 and the formation of Cu(I)4Zn4MT-3 featuring an unusual redox-inert Cu(I)4-thiolate cluster is the molecular mechanism responsible for the protective effect exerted by MT-3 towards α-Syn-Cu(II). This work provides the molecular basis for new therapeutic interventions to control the deleterious bioinorganic chemistry of α-Syn-Cu(II).

Dataset Information

Differential effects of Cu2+ and Fe3+ ions on in vitro amyloid formation of biologically-relevant ?-synuclein variants.

Publications

Differential effects of Cu<sup>2+</sup> and Fe<sup>3+</sup> ions on in vitro amyloid formation of biologically-relevant α-synuclein variants.

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