Abstract
Glutamate neurotoxicity is involved in neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. Excess glutamate causes caspase-independent programmed cell death via oxidative stress and calcium influx. Our previous study showed that calpain-1 localizes to both the cytoplasm and mitochondria, where apoptosis-inducing factor (AIF) is cleaved by calpain-1 and translocates to the nucleus to induce DNA fragmentation. The autoinhibitory region of calpain-1 conjugated with the cell-penetrating peptide HIV1-Tat (namely Tat-μCL) specifically prevents the activity of mitochondrial calpain-1 and attenuates neuronal cell death in animal models of retinitis pigmentosa, as well as glutamate-induced cell death in mouse hippocampal HT22 cells. In the present study, we constructed a lentiviral vector expressing the Tat-μCL peptide and evaluated its protective effect against glutamate-induced cell death in HT22 cells. Lentiviral transduction with Tat-μCL significantly suppressed glutamate-induced nuclear translocation of AIF and DNA fragmentation. The findings of the present study suggest that the stable expression of Tat-μCL may be a potential gene therapy modality for neurodegenerative diseases.
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Acknowledgements
We would like to thank Dr. Hiroyuki Miyoshi (RIKEN, BioResource Center) for providing the lentiviral packaging and CSII backbone plasmids. We also thank Dr. Shuya Kasai (Hirosaki University Graduate School of Medicine, Center for Advanced Medical Research) for carefully proofreading the manuscript.
Funding
The present study was supported, in part, by the Uehara Memorial Foundation, Japan, for Taku Ozaki.
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Oikawa, T., Fukuda, T., Yamashita, T. et al. Lentiviral expression of calpain-1 C2-like domain peptide prevents glutamate-induced cell death in mouse hippocampal neuronal HT22 cells. In Vitro Cell.Dev.Biol.-Animal 58, 289–294 (2022). https://doi.org/10.1007/s11626-022-00683-w
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DOI: https://doi.org/10.1007/s11626-022-00683-w