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Published on: March 15, 2024
MPP+ induces necrostatin-1- and ferrostatin-1-sensitive necrotic death of neuronal SH-SY5Y cells
Keisuke Ito1, Yutaka Eguchi2, Yusuke Imagawa3
1Laboratory 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.
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.
Insights
MPP+ causes non-apoptotic neuronal death in Parkinson
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Neurodegenerative diseases, like Parkinson's, involve complex neuronal death mechanisms.
- Current understanding of how neurons die in these conditions is incomplete, hindering effective treatments.
- Targeting cell death pathways offers potential therapeutic strategies for intractable neurological disorders.
Purpose of the Study:
- To investigate the specific mechanisms of neuronal cell death induced by 1-methyl-4-phenylpyridinium (MPP+) in a Parkinson's disease model.
- To elucidate the type of cell death triggered by MPP+ in differentiated SH-SY5Y neuroblastoma cells.
- To identify potential inhibitors and pathways involved in MPP+-induced neurotoxicity.
Main Methods:
- Utilized the human neuroblastoma cell line SH-SY5Y, differentiated to a neuronal phenotype.
- Administered 1-methyl-4-phenylpyridinium (MPP+) to induce cell death.
- Assessed cell death inhibition using necrostatin-1 (Nec-1), 3,3'-diindolylmethane (DIM), and ferroptosis inhibitors like ferrostatin-1 (Fer-1).
- Investigated involvement of RIPK1/RIPK3, p53, lipid peroxidation, ATP levels, and mitochondrial morphology.
Main Results:
- MPP+ predominantly induced non-apoptotic cell death in differentiated SH-SY5Y cells.
- This cell death was significantly inhibited by Nec-1 and DIM, but occurred independently of RIPK1/RIPK3, suggesting it is not classical necroptosis.
- MPP+-induced death was also inhibited by Fer-1, indicating some overlap with ferroptosis, but key differences were observed, including ATP depletion and mitochondrial swelling, and inhibition by Nec-1, distinguishing it from canonical ferroptosis.
Conclusions:
- MPP+-induced neuronal death in this model is a non-apoptotic process distinct from classical necroptosis and ferroptosis.
- The findings highlight a unique cell death pathway involved in MPP+-induced neurotoxicity.
- Further research into this specific non-apoptotic cell death mechanism could provide novel therapeutic targets for Parkinson's disease and other neurodegenerative disorders.
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