Lentiviral expression of calpain-1 C2-like domain peptide prevents glutamate-induced cell death in mouse hippocampal neuronal HT22 cells.

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.