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Sci Rep. 2016 Dec 5;6:38510. doi: 10.1038/srep38510.

Inhibition of alpha-synuclein aggregation by multifunctional dopamine agonists assessed by a novel in vitro assay and an in vivo Drosophila synucleinopathy model.

Author information

1
Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202,USA.
2
Department of Pharmacology, Wayne State University, Detroit, MI 48201, USA.

Abstract

Aggregation of alpha synuclein (α-syn) leading to dopaminergic neuronal death has been recognized as one of the main pathogenic factors in the initiation and progression of Parkinson's disease (PD). Consequently, α-syn has been targeted for the development of therapeutics for PD. We have developed a novel assay to screen compounds with α-syn modulating properties by mimicking recent findings from in vivo animal studies involving intrastriatal administration of pre-formed fibrils in mice, resulting in increased α-syn pathology accompanying the formation of Lewy-body (LB) type inclusions. We found that in vitro generated α-syn pre-formed fibrils induce seeding of α-syn monomers to produce aggregates in a dose-and time-dependent manner under static conditions in vitro. These aggregates were toxic towards rat pheochromocytoma cells (PC12). Our novel multifunctional dopamine agonists D-519 and D-520 exhibited significant neuroprotection in this assay, while their parent molecules did not. The neuroprotective properties of our compounds were further evaluated in a Drosophila model of synucleinopathy. Both of our compounds showed protective properties in fly eyes against the toxicity caused by α-syn. Thus, our in vitro results on modulation of aggregation and toxicity of α-syn by our novel assay were further validated with the in vivo experiments.

PMID:
27917933
PMCID:
PMC5137034
DOI:
10.1038/srep38510
[Indexed for MEDLINE]
Free PMC Article

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