title: MPP+ induces necrostatin-1- and ferrostatin-1-sensitive necrotic death of neuronal SH-SY5Y cells.
abstract: Regulation of cell death is potentially a powerful treatment modality for intractable diseases such as neurodegenerative diseases. Although there have been many reports about the possible involvement of various types of cell death in neurodegenerative diseases, it is still unclear exactly how neurons die in patients with these diseases, thus treatment strategies based on cell death regulation have not been established yet. To obtain some insight into the mechanisms of cell death involved in neurodegenerative diseases, we studied the effect of 1-methyl-4-phenylpyridinium (MPP+) on the human neuroblastoma cell line SH-SY5Y (a widely used model of Parkinson's disease). We found that MPP+ predominantly induced non-apoptotic death of neuronally differentiated SH-SY5Y cells. This cell death was strongly inhibited by necrostatin-1 (Nec-1), a necroptosis inhibitor, and by an indole-containing compound (3,3'-diindolylmethane: DIM). However, it occurred independently of receptor-interacting serine/threonine-protein kinase 1/3 (RIP1/RIP3), indicating that this form of cell death was not necroptosis. MPP+-induced cell death was also inhibited by several inhibitors of ferroptosis, including ferrostatin-1 (Fer-1). Although MPP+-induced death and ferroptosis shared some features, such as occurrence of lipid peroxidation and inhibition by Fer-1, MPP+-induced death seemed to be distinct from ferroptosis because MPP+-induced death (but not ferroptosis) was inhibited by Nec-1, was independent of p53, and was accompanied by ATP depletion and mitochondrial swelling. Further investigation of MPP+-induced non-apoptotic cell death may be useful for understanding the mechanisms of neuronal loss and for treatment of neurodegenerative diseases such as Parkinson's disease.
authors.affiliation: Laboratory of Molecular Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Molecular and Cellular Biology, Research Institute of Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-2 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan; Department of Neurology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ito
authors.affiliation: Laboratory of Molecular Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine , 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Eguchi
authors.affiliation: Department of Molecular and Cellular Biology, Research Institute of Osaka Medical Center for Cancer and Cardiovascular Diseases , 1-3-2 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Imagawa
authors.affiliation: Laboratory of Synthetic Medicinal Chemistry, Osaka University Graduate School of Pharmaceutical Sciences , 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Akai
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine , Suita, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
authors.affiliation: Department of Molecular and Cellular Biology, Research Institute of Osaka Medical Center for Cancer and Cardiovascular Diseases , 1-3-2 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Tsujimoto