Delineating the Mechanistic Insight of Inhibition of α-Synuclein Fibrillation by Neuro Metabolite, Myo-inositol: Implications in Synucleopathies-Related Disorders

Abstract

The fibrillation of α-synuclein (α-syn) is a major factor contributing to neuronal damage and is critical in developing synucleopathies-related disorders. Considering this, the discovery of new compounds that can inhibit or modulate α-syn aggregation is a significant area of research. While polyol osmolytes have been shown to reduce α-syn fibrillation, the impact of brain metabolites such as myo-inositol (MI) on α-syn aggregation has not yet been explored. This study is the first to examine the effects of MI on α-syn aggregation, utilizing spectroscopic, microscopic, and cell cytotoxicity assay. Various aggregation assays revealed that MI inhibits the α-syn fibrillation in a dose-dependent manner. Fluorescence microscopy observations suggest that MI inhibits the α-syn fibrillation by forming amorphous aggregates. MTT assay revealed that α-syn aggregates in the presence of different concentrations of MI were not toxic as compared to α-syn fibrils. Thus, the mechanistic insight of inhibition of α-syn fibrillation by MI was explored by employing interaction studies using spectroscopic, calorimetric, and in silico approaches. Surface plasmon resonance and isothermal titration calorimetry suggest that MI-α-syn interacted with significant binding affinity, and the reaction was spontaneous. Molecular docking results depict that MI interacted with the aggregation-prone residues (36-42) at the N-terminal of α-syn, thereby stabilizing the α-syn and preventing the fibril formation. Molecular dynamics simulation results demonstrate the stability of the complex formation of MI with α-syn. This study highlighted the mechanistic insight of MI on preventing the α-syn from forming amyloid fibril, which could be further explored for therapeutic management of synucleopathies-related disorders.

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