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 reentry 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 an 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 ␤ 1-42 peptide (A␤ 42 ) treatment of cortical neurons suppressed miR-34a, resulting in unscheduled cell cycle reentry, which resulted in apoptosis. The repression of miR-34a was a result of degradation of TAp73, which was mediated by aberrant activation of the MEK extracellular signal-regulated kinase (ERK) pathway by A␤ 42 . A significant decrease in miR-34a and TAp73 was observed in the cortex of a transgenic (Tg) mouse model of AD, which correlated well with cell cycle reentry observed in the neurons of these animals. Importantly, the overexpression of TAp73␣ and miR-34a reversed cell cyclerelated 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. Neurons exit the cell cycle upon terminal differentiation, and their cell cycle remains suppressed to maintain the state of differentiation. There is substantial evidence which indicates that neurons can reenter the cell cycle and also undergo DNA replication. However, this attempt, which typically may occur in response to neurotoxic insults like beta amyloid peptide A␤ 42 and DNA-damaging agents, leads to neuronal death but not mitosis (1-4). The role of several cell cycle proteins seems to be distinct from the cell cycle in neurons. G 1 -S transition in the mammalian cell cycle is initiated as a result of production of D-type cyclins, which complex with their cognate partner cdk4/6. Cyclin D-cdk4/ 6-mediated phosphorylation of Rb causes its dissociation from E2F, resulting in its transcriptional activation (5). E2F transcribes genes like the cyclin E gene, which are important for S-phase progression. In terminally differentiated neurons, this pathway remains largely shut down. The process of neuronal differentiation is dependent on Rb, as its knockout results in dedifferentiation and cell cycle reentry (6) in an E2F-1-dependent manner (7), indicating that it is critical for the cell cycle machinery to remain suppressed for the health of the neuron.Although the link between neuronal cell cycle reentry has been reported for several neurodegenerative disorders (8), it is best studied for Alzheimer's disease (AD) (8, 9). Several lines of evidence implicate aberrant cell cycle reentry of neurons in the brains of AD patients, which may contribute to neuronal loss (10, 11). Studies on various in vitro and animal models of neurodegenerative disorders like AD indicate that the enhanc...

Role and regulation of p27 in neuronal apoptosis

“…The neurons from Tg AD exhibited elevated expression of cleaved caspase 3 as reported previously (Modi et al . ), which was significantly prevented by p27 depletion (Fig. a, panel d, lane 3 vs. lane 2).…”

“…; Modi et al . ). The neurons from Tg AD exhibited elevated expression of cleaved caspase 3 as reported previously (Modi et al .…”

“…As reported earlier, Tg AD neurons exhibit aberrant expression of cyclin D1 (Modi et al . ), which results in dissociation of Cdk5 from p35 (Fig. b, panel b, lane 2 vs. lane 1) and reduced p35‐Cdk5 activity (Fig.…”

“…Since expression of cyclin D1 is low in these cells as a result of neuronal differentiation, it was over‐expressed, using adenoviruses (Modi et al . , ) and p27 was knocked down, using specific siRNA. While Cdk5/cyclin D1 binding was observed, it was significantly reduced upon p27 knockdown (Fig.…”

Maternal immune activation alters brain microRNA expression in mouse offspring

“…Modi et al. reported that miR‐34a targeted cyclin D1 and promoted neuronal differentiation by inhibiting cell cycle reentry, while downregulation of miR‐34a caused cell cycle‐related neuronal apoptosis 46. Fear memory consolidation was also mediated by miR‐34, which inhibits the Notch signaling pathway in the amygdala 47.…”