Neuronal cell cycle: the neuron itself and its circumstances

Abstract

Neurons are usually regarded as postmitotic cells that undergo apoptosis in response to cell cycle reactivation. Nevertheless, recent evidence indicates the existence of a defined developmental program that induces DNA replication in specific populations of neurons, which remain in a tetraploid state for the rest of their adult life. Similarly, de novo neuronal tetraploidization has also been described in the adult brain as an early hallmark of neurodegeneration. The aim of this review is to integrate these recent developments in the context of cell cycle regulation and apoptotic cell death in neurons. We conclude that a variety of mechanisms exists in neuronal cells for G1/S and G2/M checkpoint regulation. These mechanisms, which are connected with the apoptotic machinery, can be modulated by environmental signals and the neuronal phenotype itself, thus resulting in a variety of outcomes ranging from cell death at the G1/S checkpoint to full proliferation of differentiated neurons.

Exploring and exploiting the systemic effects of deregulated replication licensing

“…Intriguingly, apart from developmental and neoplastic diseases, cell cycle re-entry and DNA replication in neurons has been linked to neural degeneration and injury. Although terminally differentiated neurons are typically in a quiescent state having blocked their ability to Page 9 of 26 A c c e p t e d M a n u s c r i p t 9 proliferate, several regulators of G1 to S-phase transition are expressed in normal adult brain and could lead to cell cycle re-activation under specific circumstances such as neurotrophic factor deprivation, DNA damage and oxidative stress [92]. Neuronal cell cycle re-activation is normally followed by apoptosis even before signs of DNA synthesis in G1/S checkpoint [93][94] or after DNA replication [95].…”

“…Neuronal cell cycle re-activation is normally followed by apoptosis even before signs of DNA synthesis in G1/S checkpoint [93][94] or after DNA replication [95]. However, increasing evidence suggest that postmitotic neurons can re-enter cell cycle, replicate their genome and survive with a twofold DNA content in several degenerative diseases (reviewed in [92] and [96]). Particularly, CDKand Cdc7-dependent MCM2 phosphorylation at Ser40/41 was observed in the cytoplasm of neurons from patients with Alzheimer disease, a strong indication of cell cycle re-entry and active DNA replication [97].…”

RA Differentiation Enhances Dopaminergic Features, Changes Redox Parameters, and Increases Dopamine Transporter Dependency in 6-Hydroxydopamine-Induced Neurotoxicity in SH-SY5Y Cells

“…1 in Electronic supplementary material). Moreover, the cell cycle arrest in G2-M is commonly found in neurodegenerative diseases such and PD, where some populations of neurons complete DNA synthesis and are able to pass through the S phase, but are arrested at the G2/M (Frade and Ovejero-Benito 2015).…”

Metformin Protects Neurons against Oxygen-Glucose Deprivation/Reoxygenation -Induced Injury by Down-Regulating MAD2B

“…Mature neurons do not undergo cell proliferation and, if lost, are not replaced [24]. Recently, numerous studies have suggested that when the neurons are exposed into some conditions such as oxidative damage, target deprivation, DNA damage, they may reenter the cell cycle from G0 phase [25]. Moreover, once neurons re-entry the cell cycle, most of them always die.…”