Objective: To investigate whether eEF1A2 promotes neuronal survival through PI3K/Akt/mTOR pathway in a toxin-induced Parkinson’s disease model.

Background: Parkinson’s disease is a common neurodegenerative disorder characterized by loss of dopaminergic neurons in substantia nigra pars compacta. Its molecular pathogenesis is not fully understood, which needs to be elucidated. Eukaryotic protein elongation factor 1 alpha 2 (eEF1A2) is a translation elongation factor involved in protein synthesis. It is only expressed in tissues of normal brain, heart, and skeletal muscle. Several studies revealed that eEF1A2 contributes cell protection against apoptotic cell death likely through the PI3K/Akt activation. Our previous study has also shown a correlated expression of eEF1A2 with the PI3K/Akt/mTOR pathway in a cellular model of Parkinson’s disease.

Methods: The study was performed by using MPP+ to induce cell death in retinoic acid-differentiated neuroblastoma SH-SY5Y cells. To confirm whether eEF1A2 plays pro-survival role through PI3K/Akt/mTOR pathway, we conducted RNAi knockdown of eEF1A2. Expression of eEF1A2, PI3Ks, Akt, and mTOR was evaluated using real-time PCR and western blot analysis. PI3K inhibitors (LY294002 and wortmanin) were also used for studying the PI3K/Akt/mTOR signaling pathway.

Results: The result showed a significant positive correlation between the upregulation of both eEF1A2 and PI3K/Akt/mTOR pathway, suggesting that eEF1A2 might mediate cell survival and protect against toxin-induced apoptosis through Akt activation. Inactivation of eEF1A2 by siRNA reduced Akt activity and promoted apoptosis cell death by upregulation of cleaved-caspase-3 at both mRNA and protein levels. Inhibition of Akt activity by PI3K inhibitors induced upregulation of eEF1A2; however, it could not promote cell survival and protect against toxin-induced apoptosis in the Parkinson’s disease model.

Conclusions: These findings suggested that reduced eEF1A2 expression may affect cell survival of MPP+-treated SH-SY5Y dopaminergic cells through the PI3K/Akt/mTOR pathway.

References: 1. Khwanraj, K.; Madlah, S.; Grataitong, K.; Dharmasaroja, P. Comparative mRNA Expression of eEF1A Isoforms and a PI3K/Akt/mTOR Pathway in a Cellular Model of Parkinson’s Disease. Parkinsons Dis. 2016, 2016: 8716016. 2. Pellegrino, R.; Calvisi, D. F.; Neumann, O.; Kolluru, V.; Wesely, J.; Chen, X.; Wang, C.; Wuestefeld, T.; Ladu, S.; Elgohary, N.; Bermejo, J. L.; Radlwimmer, B.; Zornig, M.; Zender, L.; Dombrowski, F.; Evert, M.; Schirmacher, P.; Longerich, T. EEF1A2 inactivates p53 by way of PI3K/AKT/mTOR-dependent stabilization of MDM4 in hepatocellular carcinoma. Hepatology. 2014, 59(5), 1886-1899.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/knockdown-of-eef1a2-reduced-neuronal-survival-in-a-sh-sy5y-cellular-model-of-parkinsons-disease-through-the-pi3k-akt-mtor-pathway/