title: Neurotoxin β‑N‑methylamino‑L‑alanine induces endoplasmic reticulum stress‑mediated neuronal apoptosis.
abstract: β-N-methylamino-L-alanine (BMAA) is a neurotoxin that is closely associated with the incidence of amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease. In cultured neuronal cells, BMAA notably induces the upregulation of endoplasmic reticulum (ER) chaperons and activates the unfolded protein response (UPR) receptor pathways of protein kinase RNA‑like endoplasmic reticulum kinase, inositol‑requiring kinase 1 and transcription factor 6. The ER stress‑specific protein CCAAT/‑enhancer‑binding protein homologous protein (CHOP) affords pro‑apoptotic responses that cause mitochondrial damage and caspase activation. BMAA also induces the activation of mitogen‑activated protein kinase member c‑JUN N‑terminal kinase, p38 and extracellular signal‑regulated kinase, which have been suggested to be involved in the signaling pathway of UPR‑mediated apoptosis. Inhibition of ER stress using ER stress antagonist, salubrinal, attenuated the expression of CHOP and alleviated neuronal death. Overexpression of heat shock protein 70 suppressed the activation of UPR receptors and UPR‑evoked apoptotic signaling. The present findings demonstrated that ER stress induced by BMAA is the important mediator of neuronal injury and apoptotic death, and suggests development in novel therapeutic strategies for treatment.
authors.affiliation: Department of Biochemistry and Molecular Biology (BK21 Project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130‑701, Republic of Korea.
authors.forename: Haiying
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Biochemistry and Molecular Biology (BK21 Project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130‑701, Republic of Korea.
authors.forename: Kiyoon
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology (BK21 Project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130‑701, Republic of Korea.
authors.forename: Yoojung
authors.initials: Y
authors.lastname: Oh
authors.affiliation: Department of Biochemistry and Molecular Biology (BK21 Project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130‑701, Republic of Korea.
authors.forename: Kyung Sik
authors.initials: KS
authors.lastname: Yoon
authors.affiliation: Department of Biochemistry and Molecular Biology (BK21 Project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130‑701, Republic of Korea.
authors.forename: Hyung Hwan
authors.initials: HH
authors.lastname: Baik
authors.affiliation: Department of Biochemistry and Molecular Biology (BK21 Project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130‑701, Republic of Korea.
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology (BK21 Project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130‑701, Republic of Korea.
authors.forename: Joohun
authors.initials: J
authors.lastname: Ha
authors.affiliation: Department of Biochemistry and Molecular Biology (BK21 Project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130‑701, Republic of Korea.
authors.forename: Insug
authors.initials: I
authors.lastname: Kang
authors.affiliation: Department of Biochemistry and Molecular Biology (BK21 Project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130‑701, Republic of Korea.
authors.forename: Wonchae
authors.initials: W
authors.lastname: Choe
mesh_terms: D000599:Amino Acids, Diamino / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D000087522:Cyanobacteria Toxins; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D000599:Amino Acids, Diamino; D000087522:Cyanobacteria Toxins; D018840:HSP70 Heat-Shock Proteins; D009498:Neurotoxins; C001824:beta-N-methylamino-L-alanine; D051742:Transcription Factor CHOP