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Towards an Integrative Understanding of tRNA Aminoacylation–Diet–Host–Gut Microbiome Interactions in Neurodegeneration

1,2,3,* and 2,4
1
Expert Biomed, Inc., 11933 SW 271st TER Homestead, Miami Dade, FL 33032-3305, USA
2
Stop Alzheimers Corp., Miami Dade, FL 33032, USA
3
Nova Southeastern University, 3301 College Ave, Fort Lauderdale, FL 33314, USA
4
University of Texas at San Antonio, 1 UTSA Circle, San Antonio, TX 78249, USA
*
Author to whom correspondence should be addressed.
Nutrients 2018, 10(4), 410; https://doi.org/10.3390/nu10040410
Received: 14 February 2018 / Revised: 19 March 2018 / Accepted: 22 March 2018 / Published: 26 March 2018
(This article belongs to the Special Issue Brain Aging and Gut-Brain Axis)
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Abstract

Transgenic mice used for Alzheimer’s disease (AD) preclinical experiments do not recapitulate the human disease. In our models, the dietary tryptophan metabolite tryptamine produced by human gut microbiome induces tryptophanyl-tRNA synthetase (TrpRS) deficiency with consequent neurodegeneration in cells and mice. Dietary supplements, antibiotics and certain drugs increase tryptamine content in vivo. TrpRS catalyzes tryptophan attachment to tRNAtrp at initial step of protein biosynthesis. Tryptamine that easily crosses the blood–brain barrier induces vasculopathies, neurodegeneration and cell death via TrpRS competitive inhibition. TrpRS inhibitor tryptophanol produced by gut microbiome also induces neurodegeneration. TrpRS inhibition by tryptamine and its metabolites preventing tryptophan incorporation into proteins lead to protein biosynthesis impairment. Tryptophan, a least amino acid in food and proteins that cannot be synthesized by humans competes with frequent amino acids for the transport from blood to brain. Tryptophan is a vulnerable amino acid, which can be easily lost to protein biosynthesis. Some proteins marking neurodegenerative pathology, such as tau lack tryptophan. TrpRS exists in cytoplasmic (WARS) and mitochondrial (WARS2) forms. Pathogenic gene variants of both forms cause TrpRS deficiency with consequent intellectual and motor disabilities in humans. The diminished tryptophan-dependent protein biosynthesis in AD patients is a proof of our model-based disease concept. View Full-Text
Keywords: tryptophan frequency; tryptamine in diet; protein biosynthesis; tryptophanyl-tRNA synthetase deficiency and gene mutations; neurodegeneration; tripeptides; Alzheimer’s disease; gut microbiome; vasculopathies tryptophan frequency; tryptamine in diet; protein biosynthesis; tryptophanyl-tRNA synthetase deficiency and gene mutations; neurodegeneration; tripeptides; Alzheimer’s disease; gut microbiome; vasculopathies
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Paley, E.L.; Perry, G. Towards an Integrative Understanding of tRNA Aminoacylation–Diet–Host–Gut Microbiome Interactions in Neurodegeneration. Nutrients 2018, 10, 410.

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