Loss of MECP2 Leads to Activation of P53 and Neuronal Senescence

Ohashi, Masao; Korsakova, E; Allen, Denise E.; Lee, Peiyee; Fu, Kai; Vargas, Benni; Cinkornpumin, Jessica; Salas, Carlos; Park, Jenny C.; Germanguz, Igal; Langerman, Justin; Chronis, Constantinos; Kuoy, Edward; Tran, Stephen; Xiao, Xinshu; Pellegrini, Matteo; Plath, Kathrin; Lowry, William E.

doi:10.1016/j.stemcr.2018.04.001

Cited by 62 publications

(69 citation statements)

References 42 publications

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“…The fusion organoid system is highly amenable to such detailed cellular and circuit analyses and provides unprecedented opportunities for modeling neural network dysfunction associated with a variety of human neurological disorders. and ganglionic eminence (GE) organoids were generated from the H9 hPSC line 41 or Rett hiPSCs 30 as described previously 15 Following initial imaging in the absence of drugs, organoids were then subjected to 1-minute incubation with the GABAA receptor antagonist gabazine (25 µM) or bicuculline methiodide (100 µM) and the identical fields were re-imaged after drug exposure.…”

Section: Discussionmentioning

confidence: 99%

“…For example, a recent hiPSC-based study has suggested that Rett may impact prenatal neurogenesis through microRNA-mediated changes in AKT and ERK activity 26 . Interestingly, while neuroanatomical changes in dendritic arborization and spine density have been reported in multiple Rett models 25,[27][28][29][30] , gross structural abnormalities are less prevalent.…”

Section: Rett Syndrome Fusion Organoids Exhibit Hypersynchronous Neurmentioning

confidence: 99%

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Identification of neural oscillations and epileptiform changes in human brain organoids

Samarasinghe

Miranda

Buth

et al. 2019

Preprint

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Human brain organoids represent a powerful tool for the study of human neurological diseases particularly those that impact brain growth and structure. However, many neurological diseases lack obvious anatomical abnormalities, yet significantly impact neural network functions, raising the question of whether organoids possess sufficient neural network architecture and complexity to model these conditions. Here, we explore the network level functions of brain organoids using calcium sensor imaging and extracellular recording approaches that together reveal the existence of complex oscillatory network behaviors reminiscent of intact brain preparations. We further demonstrate strikingly abnormal epileptiform network activity in organoids derived from a Rett Syndrome patient despite only modest anatomical differences from isogenically matched controls, and rescue with an unconventional neuromodulatory drug Pifithrin-a. Together, these findings provide an essential foundation for the utilization of human brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery.

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Section: Discussionmentioning

confidence: 99%

Section: Rett Syndrome Fusion Organoids Exhibit Hypersynchronous Neurmentioning

confidence: 99%

Identification of neural oscillations and epileptiform changes in human brain organoids

Samarasinghe

Miranda

Buth

et al. 2019

Preprint

Self Cite

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“…In the aging rat brain, p53 is upregulated compared to young animals [23]. Moreover, in hiPSCs-derived neurons carrying a loss-of-function mutation of the MECP2 gene causing intellectual disability (Rett syndrome), the mutation-associated induction of p53 is associated with a senescence-like phenotype directly in neurons [24]. With further support, p53 is required for the manifestation of hyperinsulinemia-triggered senescence in terminally differentiated adipocytes [7].…”

Section: Atypical Neuronal Cell Cycle Activity and Pseudomitosenescencementioning

confidence: 94%

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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“…Along with functional changes, aged cortical neurons showed alterations in molecular hallmarks associated with neuronal senescence [45][46][47] . We found that aged neurons exhibit higher expression levels of p53 and increased activation of pJNK and pP38, three molecules implicated in neuronal demise 48,49 .…”

Section: Age-related Functional and Molecular Changes On Cultured Cormentioning

confidence: 99%

Inhibition ofde novoceramide biosynthesis affects aging phenotype in anin vitromodel of neuronal senescence

Granzotto

Bomba

Castelli

et al. 2019

Preprint

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Although aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be delayed, counteracted, if not completely interrupted. Aging is the primary risk factor for the onset and development of neurodegenerative conditions like Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Intracellular calcium (Ca 2+ i) dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are critical factors that contribute to senescence-related processes. Ceramides, a class of sphingolipids involved in a wide array of biological functions, are important mediators of cellular senescence, but their role in neuronal aging is still largely unexplored.In this study, we investigated the effects of L-cycloserine (L-CS), an inhibitor of de novo ceramide biosynthesis, on the aging phenotype of cortical neurons that have been maintained in culture for 22 days, a setting employed as an in vitro model of cellular senescence. Our findings indicate that 'aged' neurons display, when compared to control cultures, overt dysregulation of cytosolic and subcellular [Ca 2+ ]i levels, mitochondrial dysfunction, increased reactive oxygen species generation, altered synaptic activity as well as the activation of neuronal death-related molecules. Treatment with L-CS (30 µM) positively affected the senescent phenotype, a result accompanied by recovery of neuronal [Ca 2+ ]i signaling, and reduction of mitochondrial dysfunction and reactive oxygen species generation.The results suggest that the de novo ceramide biosynthesis may represent a critical intermediate in the molecular and functional cascade leading to neuronal senescence. Our findings also identify ceramide biosynthesis inhibitors as promising pharmacological tools to decrease agerelated neuronal dysfunctions. L-CS treatment does not modify NCX activityCeramides can modulate the activity of the plasmalemmal Na + -Ca 2+ exchanger (NCX) 25 , a low capacitance high-affinity system that critically regulates cellular [Ca 2+ ]i. We, therefore, investigated

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Loss of MECP2 Leads to Activation of P53 and Neuronal Senescence

Cited by 62 publications

References 42 publications

Identification of neural oscillations and epileptiform changes in human brain organoids

Identification of neural oscillations and epileptiform changes in human brain organoids

Amitosenescence and Pseudomitosenescence: Putative New Players in the Aging Process

Inhibition ofde novoceramide biosynthesis affects aging phenotype in anin vitromodel of neuronal senescence

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