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

Abstract

Growing evidence suggests that human gut bacteria, which comprise the microbiome, are linked to several neurodegenerative disorders. An imbalance in the bacterial population in the gut of Parkinson’s disease (PD) and Alzheimer’s disease (AD) patients has been detected in several studies. This dysbiosis very likely decreases or increases microbiome-derived molecules that are protective or detrimental, respectively, to the human body and those changes are communicated to the brain through the so-called ‘gut-brain-axis’. The microbiome-derived molecule queuine is a hypermodified nucleobase enriched in the brain and is exclusively produced by bacteria and salvaged by humans through their gut epithelium. Queuine replaces guanine at the wobble position (position 34) of tRNAs with GUN anticodons and promotes efficient cytoplasmic and mitochondrial mRNA translation. Queuine depletion leads to protein misfolding and activation of the endoplasmic reticulum stress and unfolded protein response pathways in mice and human cells. Protein aggregation and mitochondrial impairment are often associated with neural dysfunction and neurodegeneration. To elucidate whether queuine could facilitate protein folding and prevent aggregation and mitochondrial defects that lead to proteinopathy, we tested the effect of chemically synthesized queuine, STL-101, in several in vitro models of neurodegeneration. After neurons were pretreated with STL-101 we observed a significant decrease in hyperphosphorylated alpha-synuclein, a marker of alpha-synuclein aggregation in a PD model of synucleinopathy, as well as a decrease in tau hyperphosphorylation in an acute and a chronic model of AD. Additionally, an associated increase in neuronal survival was found in cells pretreated with STL-101 in both AD models as well as in a neurotoxic model of PD. Measurement of queuine in the plasma of 180 neurologically healthy individuals suggests that healthy humans maintain protective levels of queuine. Our work has identified a new role for queuine in neuroprotection uncovering a therapeutic potential for STL-101 in neurological disorders.

Are Metabolites From the Gut Microbiota Capable of Regulating Epigenetic Mechanisms in the Human Parasite Entamoeba histolytica?

“…Eukaryotes are not capable of Q synthesis and rely on salvage of the queuine base as a Q precursor either by nutrition or by the intestinal bacterial flora ( Farkas, 1980 ; Katze et al, 1982 ; Ott et al, 1982 ). Queuine has been associated with neuroprotection ( Richard et al, 2021 ) whereas absence of queuine is associated with better cancer cells growth and survival by promoting Warburg metabolism ( Hayes et al, 2020 ). The tRNA-guanine transglycosylase (TGT) is the main enzyme responsible for the formation of Q in the anticodon loop position 34 of tRNA Asp , tRNA His , tRNA Asn and tRNA Tyr .…”

Analysis of queuosine and 2-thio tRNA modifications by high throughput sequencing

“…In mammals, gut availability of queuine affects virulence of resident gut microbes ( 10 ) and modulates cancer growth ( 11 , 12 ). Q-modification levels in tRNA are especially high in human brain tissues ( 13 ) and queuine also plays a role in resistance to cancer metabolism ( 11 ) and neuronal damage ( 14 ). Since queuine must be scavenged from the gut and Q-tRNA modification is directly involved in protein biosynthesis, queuine and Q-tRNA modification present a clear connection between the gut microbiome and host proteostasis.…”

Functional integration of a semi-synthetic azido-queuosine derivative into translation and a tRNA modification circuit

“…In spite of numerous described Q-dependent implications in various diseases, starting from cancer ( 29–32 ) to neurological and neuropsychiatric disorders, such as multiple sclerosis, schizophrenia and Parkinson ( 79 , 80 , 33 , 34 ), a defined mechanism explaining the role of Q in these pathologies is still missing ( 28 ). Recently, we discovered a direct connection between Q, accuracy and the speed of codon-biased translation ( 27 , 28 ), which promotes protein folding and prevents the accumulation of misfolded proteins.…”

“…In vivo studies in eukaryotes likewise reported an impact on the decoding process, enabling decoding of synonymous codons by wobble base pairing ( 22 , 25 , 26 ), and affecting translation speed and accuracy ( 27 , 28 ). Queuosine's multifaceted involvement in the cellular machinery was reported to be associated with cancer ( 29–32 ), neuronal disorders ( 33–35 ) as well as bacterial and parasitic infection ( 36 , 37 ). Consequently, the perception of therapeutic potential associated with its biogenesis has consistently increased, in keeping with a general trend in epitranscriptomics…”