Primary neurons can enter M-phase

Walton, Chaska C.; Zhang, Wei; Patiño-Parrado, Iris; Barrio-Alonso, Estíbaliz; Garrido, Juan J.; Frade, José Marı́a

doi:10.1038/s41598-019-40462-4

Cited by 28 publications

(30 citation statements)

References 76 publications

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“…The reduction of dendritic length and branching observed in TAg-lipofected neurons is consistent with studies carried out with mouse models of AD and postmortem material from AD patients in which a reduction in the total dendritic area was evident (Moolman et al, 2004). Interestingly, this reduction of dendritic length and branching mimics what has been observed in mitotic neurons induced to reactivate the cell cycle with a truncated form of cyclin E/Cdk2 (Walton et al, 2019).…”

Section: Morphological Changes Induced By Cell Cycle Reentry In Cortisupporting

confidence: 88%

Pathological Aspects of Neuronal Hyperploidization in Alzheimer’s Disease Evidenced by Computer Simulation

et al. 2020

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When subjected to stress, terminally differentiated neurons are susceptible to reactivate the cell cycle and become hyperploid. This process is well documented in Alzheimer's disease (AD), where it may participate in the etiology of the disease. However, despite its potential importance, the effects of neuronal hyperploidy (NH) on brain function and its relationship with AD remains obscure. An important step forward in our understanding of the pathological effect of NH has been the development of transgenic mice with neuronal expression of oncogenes as model systems of AD. The analysis of these mice has demonstrated that forced cell cycle reentry in neurons results in most hallmarks of AD, including neurofibrillary tangles, Aβ peptide deposits, gliosis, cognitive loss, and neuronal death. Nevertheless, in contrast to the pathological situation, where a relatively small proportion of neurons become hyperploid, neuronal cell cycle reentry in these mice is generalized. We have recently developed an in vitro system in which cell cycle is induced in a reduced proportion of differentiated neurons, mimicking the in vivo situation. This manipulation reveals that NH correlates with synaptic dysfunction and morphological changes in the affected neurons, and that membrane depolarization facilitates the survival of hyperploid neurons. This suggests that the integration of synaptically silent, hyperploid neurons in electrically active neural networks allows their survival while perturbing the normal functioning of the network itself, a hypothesis that we have tested in silico. In this perspective, we will discuss on these aspects trying to convince the reader that NH represents a relevant process in AD.

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Section: Morphological Changes Induced By Cell Cycle Reentry In Cortisupporting

confidence: 88%

Pathological Aspects of Neuronal Hyperploidization in Alzheimer’s Disease Evidenced by Computer Simulation

et al. 2020

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“…Estimates suggest that up to 13%-40% of inflicted neurons can adopt a state of G 0 exit [13], paralleled by the upregulation of several Cdks and the suppression of Cdk inhibitors (Cdkls), as indicated by our own studies-a state we therefore term 'replicative reprogramming'. Such evidence, as well as the recent attempt to force a completed neuromitosis in differentiated cultured neurons [14], suggests that neurons retain a functional cell cycle machinery also in their differentiated state, as illustrated in Figure 1. This endowment includes the activating (Cdks) as well as inhibitory (CdkIs) branch of cell cycle regulators, which can connect atypical cell cycle to both cell cycle progression and apoptosis, and to senescence.…”

Section: Atypical Neuronal Cell Cycle Activity and Pseudomitosenescencementioning

confidence: 88%

Amitosenescence and Pseudomitosenescence: Putative New Players in the Aging Process

Wengerodt

Schmeer

Witte

et al. 2019

Cells

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Replicative senescence has initially been defined as a stress reaction of replication-competent cultured cells in vitro, resulting in an ultimate cell cycle arrest at preserved growth and viability. Classically, it has been linked to critical telomere curtailment following repetitive cell divisions, and later described as a response to oncogenes and other stressors. Currently, there are compelling new directions indicating that a comparable state of cellular senescence might be adopted also by postmitotic cell entities, including terminally differentiated neurons. However, the cellular upstream inducers and molecular downstream cues mediating a senescence-like state in neurons (amitosenescence) are ill-defined. Here, we address the phenomenon of abortive atypical cell cycle activity in light of amitosenescence, and discuss why such replicative reprogramming might provide a yet unconsidered source to explain senescence in maturated neurons. We also hypothesize the existence of a G0 subphase as a priming factor for cell cycle re-entry, in analogy to discoveries in quiescent muscle stem cells. In conclusion, we propose a revision of our current view on the process and definition of senescence by encompassing a primarily replication-incompetent state (amitosenescence), which might be expanded by events of atypical cell cycle activity (pseudomitosenescence).

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“…Until recently it was assumed that such atypical cell-cycle activity will remain abortive at the latest in the S/G 2 phase and finally end up in a delayed process of apoptosis rather than the completion of cytokinesis. However, a recent work by Walton and colleagues addresses the prospective of a full ‘neuromitotic’ event based on a complex genetic and pharmacologic intervention, involving 1) cell-cycle induction by overexpression of a CyclinE/Cdk2 fusion construct, 2) apoptosis prevention via p53 inhibition, 3) G 2 checkpoint abrogation through the inhibition of Wee1 kinase, and 4) topoisomerase-2α overexpression to aid sister chromatid decatenation and cytokinesis [176]. The authors conclude from their in vitro approach that differentiated neurons are principally equipped with functional cell-cycle machinery, the progression of which seemingly follows a genuine sequence comparable to that intrinsic of replicative cells.…”

Section: Discussionmentioning

confidence: 99%

“…A further question is whether senescence markers found in post-mitotic neurons might result from the abortion of an unconventional rather than truly mitotic cell cycle. Indeed, multi-nucleation, a parameter recently utilized to identify neurons passing through an aberrant cell cycle without cell division [176], is a common signature of cellular senescence caused by oncogenic or replication stress in vitro. Thus, additional studies are required to further specify the presence, stability and functional relevance of intermediate cell-cycle states putatively intercalated between ultimate G 0 arrest and mitosis in mature neurons, also under in vivo conditions.…”

Section: Discussionmentioning

confidence: 99%

Dissecting Aging and Senescence—Current Concepts and Open Lessons

Schmeer

Kretz

Wengerodt

et al. 2019

Cells

107

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In contrast to the programmed nature of development, it is still a matter of debate whether aging is an adaptive and regulated process, or merely a consequence arising from a stochastic accumulation of harmful events that culminate in a global state of reduced fitness, risk for disease acquisition, and death. Similarly unanswered are the questions of whether aging is reversible and can be turned into rejuvenation as well as how aging is distinguishable from and influenced by cellular senescence. With the discovery of beneficial aspects of cellular senescence and evidence of senescence being not limited to replicative cellular states, a redefinition of our comprehension of aging and senescence appears scientifically overdue. Here, we provide a factor-based comparison of current knowledge on aging and senescence, which we converge on four suggested concepts, thereby implementing the newly emerging cellular and molecular aspects of geroconversion and amitosenescence, and the signatures of a genetic state termed genosenium. We also address the possibility of an aging-associated secretory phenotype in analogy to the well-characterized senescence-associated secretory phenotype and delineate the impact of epigenetic regulation in aging and senescence. Future advances will elucidate the biological and molecular fingerprints intrinsic to either process.

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Primary neurons can enter M-phase

Cited by 28 publications

References 76 publications

Pathological Aspects of Neuronal Hyperploidization in Alzheimer’s Disease Evidenced by Computer Simulation

Pathological Aspects of Neuronal Hyperploidization in Alzheimer’s Disease Evidenced by Computer Simulation

Amitosenescence and Pseudomitosenescence: Putative New Players in the Aging Process

Dissecting Aging and Senescence—Current Concepts and Open Lessons

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