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Drug targets from genetics: α-synuclein.

ABSTRACT: One of the critical issues in Parkinson disease (PD) research is the identity of the specific toxic, pathogenic moiety. In PD, mutations in α-synuclein (αsyn) or multiplication of the SNCA gene encoding αsyn, result in a phenotype of cellular inclusions, cell death, and brain dysfunction. While the historical point of view has been that the macroscopic aggregates containing αsyn are the toxic species, in the last several years evidence has emerged that suggests instead that smaller soluble species--likely oligomers containing misfolded αsyn--are actually the toxic moiety and that the fibrillar inclusions may even be a cellular detoxification pathway and less harmful. If soluble misfolded species of αsyn are the toxic moieties, then cellular mechanisms that degrade misfolded αsyn would be neuroprotective and a rational target for drug development. In this review we will discuss the fundamental mechanisms underlying αsyn toxicity including oligomer formation, oxidative stress, and degradation pathways and consider rational therapeutic strategies that may have the potential to prevent or halt αsyn induced pathogenesis in PD.

SUBMITTER: Danzer KM

PROVIDER: S-EPMC3364517 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Drug targets from genetics: α-synuclein.

Danzer Karin M KM McLean Pamela J PJ

CNS & neurological disorders drug targets 20110901 6

One of the critical issues in Parkinson disease (PD) research is the identity of the specific toxic, pathogenic moiety. In PD, mutations in α-synuclein (αsyn) or multiplication of the SNCA gene encoding αsyn, result in a phenotype of cellular inclusions, cell death, and brain dysfunction. While the historical point of view has been that the macroscopic aggregates containing αsyn are the toxic species, in the last several years evidence has emerged that suggests instead that smaller soluble speci ...[more]

PMID: 21838671

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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).

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Drug targets from genetics: α-synuclein.

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Drug targets from genetics: α-synuclein.

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