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SpeedyRINGO as a neuroprotector in neurodegeneration

Yesim Kaya

Statement of the Problem: Neurodegeneration is the progressive loss of function and structure of neurons that cause neuronal cell death. Although neurodegeneration is a multifactorial process, one of the main causative factors is elevated intracellular calcium levels which leads to apoptosis by inducing p53, thus negatively affecting two pathways: mitogenic extracellular signal-regulated kinase/mitogen activated protein kinase(ERK/MAPK) and survival phosphoinositide 3-kinase/protein kinaseB(PI3K/AKT) pathways. Speedy/rapid inducer of G2/M progression in oocytes (Speedy/RINGO) is a cell cycle regulatory protein that increases survival of p53-positive mitotic cells by inhibiting the apoptosis. Moreover, we showed for the first time that this protein elicits p53-dependent anti-apoptotic effects in calcium-induced degenerated primary hippocampal neurons. Methodology&Theoretical Orientation: Our laboratory is currently investigating whether Speedy/RINGO exerts this anti-apoptotic function through ERK/MAPK and PI3K/AKT pathways. For this purpose, we used undifferentiated p53 and Speedy/RINGO-expressing neuronal-like neuroblastoma cells as preliminary model. Findings: Our previous investigations indicated that Speedy/RINGO protects neurons against calcium-mediated p53-dependent apoptosis without decreasing p53 levels. This finding implies that the anti-apoptotic effect of Speedy/RINGO is downstream of p53 activation, not directly on p53 itself. The most remarkable downstream targets of p53, in terms of generating an apoptotic effect on neurons, are ERK/MAPK and PI3K/AKT pathways. Within this context, silencing of the Speedy/RINGO gene significantly alters expression levels and phosphorylation states of certain members of these pathways. This leads to apoptotic death of neuroblastoma cells, likely due to the absence of Speedy/RINGO’s regulatory function on these two pathways. Conclusion & Significance: Preliminary data indicates that Speedy/RINGO plays an essential role on the regulation of ERK/MAPK and PI3K/AKT pathways that directly affect the apoptotic state and survival rate of cells giving insights about molecular mechanism of Speedy/RINGO in neuronal survival. However, to understand the exact mechanism of Speedy/RINGO’s anti-apoptotic function in neurons, studies is being performed in our laboratory both with in vitro degenerated primary neuron models.