title: Tryptamine-induced tryptophanyl-tRNAtrp deficiency in neurodifferentiation and neurodegeneration interplay: progenitor activation with neurite growth terminated in Alzheimer's disease neuronal vesicularization and fragmentation.
abstract: Tryptophanyl-tRNA synthetase (TrpRS) catalyzes tryptophanyl-tRNAtrp formation. At concentrations exceeding tryptophan, tryptamine inhibits TrpRS. This leads in tryptophanyl-tRNA deficiency and synthesis of aberrant proteins. Tryptamine presents in food and crosses blood-brain barrier. The purpose of this study is to test the hypothesis that tryptamine-induced changes in cell and animal models correlate with Alzheimer's disease (AD) manifestations. Tryptamine prevented growth of human neuroblastoma. Epithelioids recovered growth in tryptamine-free medium, while neuroblasts died. Tryptamine induced epithelioid differentiation forming synaptic vesicles, neuritic contacts, and TrpRS+ axons in stable sublines. A fraction of epithelioids was adhered to satellite cells via trypsin-resistant interdigitating junctions. Tryptamine stimulated satellite division and differentiation into neurons, transitional cell variants and neuroblasts able to repopulate. Both tryptamine-inhibited and hypoxia-downregulated TrpRS translocates into cytoplasmic extensions. TrpRS is secreted into extracellular space as a free protein or within vesicles extended from cytoplasm and then pinched-off from plasma membrane of tryptamine-treated cells. Extracellular vesicles fuse in congophilic TrpRS+ plaques in tryptamine-treated culture and AD brain. TrpRS prominent immunoreactivity is associated with plasma and vesicle membranes of satellites and AD brain degenerated neurons. Tryptamine-modified mouse brain expresses amyloid and abnormal filaments in extracellular and neuronal plasma membrane vesicles. Radiolabeled tryptamine, tryptophan and serotonin uptake was 10-fold lower in tryptamine-resistant compared to tryptamine-sensitive cells. In both variants, tryptamine uptake exceeded tryptophan uptake within 2-h assuring TrpRS inhibition. Here, tryptophanyl-tRNAtrp deficiency implicates in both neurite growth and termination/collapse. Neurite growth termination prompts TrpRS+ vesicularization. TrpRS+ vesicles contribute in neuronal fragmentation and fibrillar-vesicular congophilic plaques in AD brain.
authors.affiliation: Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale-Davie, Florida, USA. ep180@nova.edu
authors.forename: Elena L
authors.initials: EL
authors.lastname: Paley
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D009410:Nerve Degeneration / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D014363:Tryptamines / Q000494:pharmacology*; D014369:Tryptophan-tRNA Ligase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D014363:Tryptamines; C030820:tryptamine; D014369:Tryptophan-tRNA Ligase