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Expression of cell cycle proteins in cortical neurons-Correlation with glutamate-induced neurotoxicity
Yesim Negis1,2, Arzu Karabay1
1Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul, Turkey.
Abstract:
Under physiological conditions, upon differentiation neurons become irreversibly post-mitotic by down-regulating cell cycle progression. However, recent studies have provided evidence that aberrant expression of cell cycle related proteins; especially cyclins, cyclin-dependent kinases, and their inhibitors are accompanied by programmed cell death in neurons. This abnormal phenotype has been postulated to contribute to the pathophysiology of different neurodegenerative diseases. Glutamate is the most abundant and major excitatory neurotransmitter in the central nervous system but high concentrations are reported to be involved in the pathology of many neurodegenerative diseases. The mechanisms of glutamate neurotoxicity have been intensively investigated over the past decades but still remain not fully understood. In this study, we hypothesized that aberrant regulation of cell cycle proteins may be involved in glutamate-induced neurotoxicity in primary cultures of rat cortical neurons. The results have shown that, glutamate treatment caused apoptosis by inducing active caspase-3 and p53 expression. Together with this, an increase in cyclin D1 and Cdk4 protein levels, localization of cyclin D1 to nucleus, and a decrease in the cell cycle inhibitor p27 were observed. After glutamate treatment we also detected up-regulation of protein kinase C-α (PKC-α) protein expression. Altogether, the data reported in this study show for the first time that glutamate in cortical neurons changes simultaneously the expression levels of a number of key cell cycle proteins and cell homeostasis regulators. © 2016 BioFactors, 42(4):358-367, 2016.
Insights
Glutamate neurotoxicity in rat cortical neurons involves cell cycle dysregulation. This study shows glutamate induces apoptosis and alters key cell cycle proteins, implicating them in neurodegenerative disease pathways.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Neurons typically exit the cell cycle upon differentiation.
- Aberrant cell cycle protein expression is linked to neuronal programmed cell death and neurodegenerative diseases.
- High glutamate concentrations are implicated in neurodegenerative disease pathology, but mechanisms are unclear.
Purpose of the Study:
- To investigate the role of cell cycle protein regulation in glutamate-induced neurotoxicity.
- To examine the effects of glutamate on cell cycle proteins in primary rat cortical neurons.
Main Methods:
- Primary cultures of rat cortical neurons were treated with glutamate.
- Apoptosis was assessed by measuring active caspase-3 and p53 expression.
- Levels and localization of cell cycle proteins (cyclin D1, Cdk4, p27) and PKC-α were analyzed.
Main Results:
- Glutamate treatment induced apoptosis, evidenced by increased active caspase-3 and p53.
- Elevated cyclin D1 and Cdk4 protein levels and nuclear localization of cyclin D1 were observed.
- A decrease in the cell cycle inhibitor p27 and an increase in PKC-α were detected.
Conclusions:
- Glutamate exposure alters the expression of key cell cycle regulatory proteins in cortical neurons.
- This dysregulation of cell cycle proteins and homeostasis regulators contributes to glutamate-induced neurotoxicity.
- Findings suggest a novel mechanism linking glutamate excitotoxicity to cell cycle abnormalities in neurodegeneration.
