Title:Tryptamine Induces Axonopathy and Mitochondriopathy Mimicking Neurodegenerative Diseases via Tryptophanyl-tRNA Deficiency
VOLUME: 10 ISSUE: 9
Author(s):Elena L. Paley, George Perry and Olga Sokolova
Affiliation:Nova Southeastern University, Fort Lauderdale-Davie, Florida 33314, USA, Expert BioMed, Inc., Miami, FL, USA.
Keywords:Alzheimer’s disease, axonal swellings, mitochondria-derived vesicles, mitochondrial fission, tryptamine neurotoxicity
and nephrotoxicity, tryptophanyl-tRNA synthetase.
Abstract: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.
