Regulation of Neuronal Cell Cycle and Apoptosis by MicroRNA 34a

Abstract

The cell cycle of neurons remains suppressed to maintain the state of differentiation and aberrant cell cycle re-entry results in loss of neurons, which is a feature in neurodegenerative disorders like Alzheimer's disease (AD). Present studies revealed that the expression of microRNA-34a (miR-34a) needs to be optimal in neurons as aberrant increase or decrease in its expression causes apoptosis. miR-34a keeps the neuronal cell cycle under check by preventing the expression of cyclin D1 and promotes cell cycle arrest. Neurotoxic Amyloid β 1-42 peptide (Aβ 42 ) treatment of cortical neurons suppressed miR-34a resulting in unscheduled cell cycle re-entry, which resulted in apoptosis. The repression of miR-34a was a result of degradation of TAp73, which was mediated by aberrant activation of MEK-ERK pathway by Aβ 42 . A significant decrease in miR-34a and TAp73 was observed in the cortex of >12m old transgenic (Tg) mouse model of AD, which corroborated well with cell cycle re-entry observed in the neurons of these animals. Importantly, the overexpression of TAp73α and miR-34a reversed the Cell cycle Related Neuronal Apoptosis (CRNA). These studies provide novel insights into how modulation of neuronal cell cycle machinery may lead to neurodegeneration and may contribute to the understanding of disorders like AD.