Giulio Pasinetti, Risham Singh and Lap Ho
Icahn School of Medicine, Mount Sinai, USA
Posters & Accepted Abstracts: J Neurol Neurosci
Objective: To determine whether microbiome derived short chain fatty acid (SCFA) may modulate abnormal α-¬synuclein misfolding and seeding activity of α-synuclein to support the hypothesis of potential novel therapeutic approaches. Background: There is growing evidence from both in vivo and in vitro studies that in many neurodegenerative disorders, including synucleinopathies, cell-to-cell transmission of a pathological, misfolded protein occurs and may be a vehicle for spreading of pathology throughout the brain. We hereby investigate whether microbiota-derived SCFAs may help attenuate the misfolding of α-synuclein and their effects on seeding synucleinopathy. Design/Methods: In vitro aggregation of α-synuclein in the absence or in the presence of SCFAs at a molar ratio of 1:1 or 1:4 α¬-synuclein:SCFA, were monitored by using independent assays: photo-induced cross-linking of unmodified proteins assay, thioflavin-T, fluorescence assay, or electron microscopy. Results: We found that select microbiome-derived SCFAs significantly interfere with α-synuclein aggregation in independent in vitro assays. Conclusions: Selected microbiome-derived SCFAs may help protect against diverse synucleinopathies by converting dietary fibers into biologically available SCFAs which significantly interfere with aggregation of disease-specific α-¬synuclein into toxic aggregates. Ongoing cell-based systems, which detect levels of α-synuclein by florescent FRET signalling, will clarify the impact of this anti-aggregation activity of SCFAs on interference of α-synuclein seeding activity that is critical for the propagation of α-synuclein mediated pathologies. This data will help to clarify distinct α-synuclein seeding activity from α-synuclein isolated from post-mortem brain samples of patients with Parkinson’s disease, multiple systemic atrophies, and other synucleinopathies, leading to novel therapeutic approaches
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