Tryptamine induces axonopathy and mitochondriopathy mimicking neurodegenerative diseases via tryptophanyl-tRNA...

Neurodegeneration is induced by tryptamine, a human diet constituent, which easily crosses the blood/brain barrier. Tryptamine neurotoxicity, caused by tryptophanyl-tRNA synthetase (TrpRS) inhibition and downregulation leads to tryptophanyl-tRNA deficiency and synthesis of aberrant proteins. We identified axonal defects in hippocampus of tryptamine- treated mice similar to those observed in human brain of patients with Alzheimer's disease, multiple sclerosis and epilepsy using anti-TrpRS site-directed antibodies. The axonal defects are characterized by swellings that accumulate abnormal amounts of helical filaments and amyloid. Tryptamine produced a decreased density of somatic mitochondria concomitant with neuronal loss in mouse hippocampus. In addition, tryptamine evoked accumulation and clustering of small mitochondria in mouse hippocampus causing axonal swellings. Similarly, mitochondrial fission, fusion and clustering were revealed in human neuronal cells after tryptamine administration. Moreover the tryptamine-induced mitochondrial neuropathology includes electron-dense deposits comprising helical fibrils, cristae disruption, cristolysis, mitochondrial swelling and mitochondria-derived vesicles. TrpRS+ helical filamentous tangles formed in both neuronal and kidney cells following tryptamine treatment suggest a tryptamine broad cytotoxic repertoire in damaging vital organs. Tryptamine elicited vesicularization of inner and outer mitochondrial membranes, axonal and cell membranes. Ultrastructurally, fragmentation of swollen degenerated mitochondria, small mitochondria clustering and neurofibrillary tangles are associated with axonal membrane protrusions attributed as neuritic swellings at a lower magnification. TrpRS+ axonal swellings associated with neuropathology of patients and tryptamine-treated human cells suggest that under toxic concentrations, tryptamine is implicated as a causative agent in neurodegeneration resembling that defining a number of human diseases.