Dopaminergic neurons are constantly threatened by the thin boundaries between
functional -synuclein (AS) structural disorder and pathogenic
aggregation, and between dopamine (DA) neurotransmitter activity and accumulation
of cytotoxic by-products. The possibilities of developing drugs for Parkinson’s
disease (PD) depend on our understanding of the molecular mechanisms that cause
or accompany the pathological structural changes in AS. This review focuses on
the three interconnected aspects of AS conformational transitions, its
aggregation pathways and ligand binding. Specifically, the interactions of AS
with DA, DA metabolites, DA analogs and DA agonists are considered. Recent
advances in the field are discussed with reference to the structural properties
of AS and the methodologies employed. Although several issues are still object of
debate, salient structural features of the protein, the aggregates and the
ligands can be identified, in the hope of fueling experimental and computational
approaches to the discovery of novel disease-modifying agents.
Antonino Natalello,
Stefania Brocca,
Erika Ponzini,
Carlo Santambrogio,
Rita Grandori. Modulation of Alpha-Synuclein Conformational Ensemble and Aggregation Pathways by Dopamine and Related Molecules. Front. Biosci. (Landmark Ed)2023, 28(10), 266.
https://doi.org/10.31083/j.fbl2810266
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Fig. 1.
Pictorial representation of the main factors affecting
-synuclein (AS) aggregation. DA, dopamine; ROS, reactive oxygen
species; RNS, reactive nitrogen species; RSS, reactive sulfur species; PTMs,
post-translational modifications.
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