title: Ammonium chloride and tunicamycin are novel toxins for dopaminergic neurons and induce Parkinson's disease-like phenotypes in medaka fish.
abstract: Perturbations in protein folding and degradation are key pathological mechanisms in neurodegenerative diseases, including Parkinson's disease (PD). Recent evidence suggests that mishandling of proteins may play an important role in the pathogenesis of PD. We have utilized medaka fish to monitor the effects of injecting neurotoxins into the CSF space. In this study, ammonium chloride, tunicamycin, and lactacystin were tested for their ability to disturb lysosomal proteolysis, N-glycosylation in the endoplasmic reticulum, and proteasomal degradation, respectively. All of the substances tested induced selective loss of dopaminergic neurons, movement disorders and inclusion bodies. Among them, the features of the inclusion bodies that developed after ammonium chloride injection mimicked those of PD: co-localization of ubiquitin and phosphorylated α-synuclein, as well as the presence of LC3 protein in the inclusion bodies. Our study demonstrated that medaka fish are useful for examining the effects of environmental toxins and lysosome inhibition, and lysosome inhibitors may be factors in the development of PD.
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Matsui
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Taniguchi
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takeda
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000633:toxicity; D000643:Ammonium Chloride / Q000633:toxicity; D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D009990:Oryzias / Q000033:anatomy & histology / Q000502:physiology*; D020734:Parkinsonian Disorders / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D013378:Substantia Nigra / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D014415:Tunicamycin / Q000633:toxicity
chemical_list: D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D000643:Ammonium Chloride; D014415:Tunicamycin; C067713:lactacystin; D004298:Dopamine; D000111:Acetylcysteine