(P22-045-25) Role of Gut Microbiota-Derived Dietary Polyphenol Metabolites in α-Synuclein Misfolding Mediated Neurodegeneration

Objectives: There is growing evidence that in many neurodegenerative disorders, the cell-to-cell transmission of a pathological, misfolded protein, such as the misfolding of α-synuclein (α-syn) in Parkinson’s disease (PD).

Methods: We identified six biologically available gut microbiota-derived compounds (GMP10, GMP11, GMP26, GMP28, GMP39, and GMP44) for investigation. Using independent in vitro protein aggregation assays (e.g., photo-induced cross-linking of unmodified proteins assay, thioflavin-T, fluorescence assay, and electron microscopy), we demonstrated that three of the compounds (GMP26, GMP44, GMP28), potently inhibit aggregations of monomeric α-syn (or monomeric β-amyloid peptides) into neurotoxic protein aggregates, in vitro. Based on evidence linking the c9orf72 gene with expansions of GGGGCC hexanucleotide repeats and PD, as well as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), we continue to test the neuroprotective ability of our compounds in vivo using a Drosophila model with overexpression of GGGGCC hexanucleotide repeats.

Results: Overexpression of 30 GGGGCC repeats in the Drosophila eye causes age-dependent photoreceptor neurodegeneration (Zhang K. et al., Nature 2015; 525:56). We treated Drosophila by mixing individual test compounds into the food and found all six compounds significantly suppressed eye degeneration at 10 µM, with compounds GMP26 and GMP11 almost wholly suppressing the eye phenotype. The comparative efficacy of the six compounds is GMP26 = GMP11 > GMP39 > GMP10 > GMP44 > GMP28. Outcomes from our studies link gut microbiota with mechanisms underlying PD and suggest the feasibility of developing GMP26 as a means to simultaneously target both α-syn misfolding and C9orf72 expansion to increase the likelihood of therapeutic efficacy in PD, ALS, and FTD patients with C9orf72 expansion.

Conclusions: Our new evidence suggests the feasibility of developing the gut microbiota-derived compound(s) to simultaneously target both α-synuclein misfolding and C9orf72 hexanucleotide repeat expansion, increasing the likelihood of therapeutic efficacy in Parkinson's plus syndromes.

Funding Sources: Grant Number P50 AT008661-01 from the NCCIH. GMP holds a Senior VA Career Scientist Award from the Veterans Affairs