Queuine, a bacterial derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration

Abstract

Growing evidence suggests that human gut bacteria, comprising the microbiome that communicates with the brain through the so-called gut-brain-axis, are linked to neurodegenerative disorders. Imbalances in the microbiome of Parkinsons disease (PD) and Alzheimers disease (AD) patients have been detected in several studies. Queuine is a hypermodified nucleobase enriched in the brain and exclusively produced by bacteria and salvaged by humans through their gut epithelium. Queuine replaces guanine at the wobble position of tRNAs with GUN anticodons and promotes efficient cytoplasmic and mitochondrial mRNA translation. To elucidate whether queuine could facilitate protein folding and prevent aggregation and mitochondrial defects, hallmarks of neurodegenerative disorders, we tested the effect of chemically synthesized queuine, STL-101, in several in vitro models of neurodegeneration. Treatment with STL-101 led to increased neuronal survival as well as a significant decrease in hyper-phosphorylated alpha-synuclein, a marker of alpha-synuclein aggregation in a PD model and a decrease in tau hyperphosphorylation in an AD model. Our work has identified a new role for queuine in neuroprotection uncovering a therapeutic potential for STL-101 in neurological disorders.