Loss of neuronal cell cycle control as a mechanism of neurodegeneration in the Presenilin-1 Alzheimer's disease brain

Malik, Bilal; Currais, António; Andrés, Ana; Towlson, Christopher; Pitsi, Didier; Nunes, Ana V. M.; Niblock, Michael; Cooper, Jonathan D.; Hortobágyi, Tibor; Soriano, Salvador

doi:10.4161/cc.7.5.5427

Cited by 60 publications

(50 citation statements)

References 31 publications

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“…A recent study reported that neurons harboring the PS1 M146V FAD mutation show enhanced neuronal apoptosis associated with abnormal induction of neuronal cell cycle proteins. 42 Consistent with the role of PS-dependent regulation of PML, significantly increased levels of PML protein and mRNA were observed in samples from AD patients (FAD and SAD) compared with controls (Figures 7a and b). Interestingly, polarized PML expression was also observed in SAD patients, suggesting Reagents and antibodies.…”

Section: Discussionsupporting

confidence: 80%

Critical role of presenilin-dependent γ-secretase activity in DNA damage-induced promyelocytic leukemia protein expression and apoptosis

et al. 2013

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Promyelocytic leukemia (PML) is a major component of macromolecular multiprotein complexes called PML nuclear-bodies (PML-NBs). These PML-NBs recruit numerous proteins including CBP, p53 and HIPK2 in response to DNA damage, senescence and apoptosis. In this study, we investigated the effect of presenilin (PS), the main component of the c-secretase complex, in PML/p53 expression and downstream consequences during DNA damage-induced cell death using camptothecin (CPT). We found that the loss of PS in PS knockout (KO) MEFs (mouse embryonic fibroblasts) results in severely blunted PML expression and attenuated cell death upon CPT exposure, a phenotype that is fully reversed by re-expression of PS1 in PS KO cells and recapitulated by c-secretase inhibitors in hPS1 MEFs. Interestingly, the g-secretase cleavage product, APP intracellular domain (AICD), together with Fe65-induced PML expression at the protein and transcriptional levels in PS KO cells. PML and p53 reciprocally positively regulated each other during CPT-induced DNA damage, both of which were dependent on PS. Finally, elevated levels of PML-NB, PML protein and PML mRNA were detected in the brain tissues from Alzheimer's disease (AD) patients, where g-secretase activity is essential for pathogenesis. Our data provide for the first time, a critical role of the PS/AICD-PML/p53 pathway in DNA damage-induced apoptosis, and implicate this pathway in AD pathogenesis. Cell Death and Differentiation (2013) 20, 639-648; doi:10.1038/cdd.2012.162; published online 11 January 2012Promyelocytic leukemia (PML) protein is a well-known tumor suppressor, which functions by its association with PML-nuclear bodies (PML-NBs).1,2 PML regulates a variety of cellular processes such as induction of apoptosis, cellular senescence, inhibition of proliferation, transcription, response to DNA-damage and antiviral response.1,2 PML-NBs, which are spherical shape with a diameter of 0.2-1.0 mm, possess dynamic and heterogeneous structures.1 PML-NBs are present in most mammalian cells' nuclei, numbers that typically range from 5-15 bodies per nucleus depending on the cell type, cell cycle and differentiation stage of the cell. 1As PML KO mice are resistant to proapoptotic stimuli 3 and overexpression of PML prohibits tumor formation in nude mice, 4 the tumor suppressive and pro-apoptotic roles of these structures are well established. Indeed, PML KO cells are protected against both p53-dependent and -independent apoptotic stimuli, such as infrared, interferon, TNF-a and ceramide.5 Moreover, PML has been found to physically associate with critical apoptosis regulators including p53, pRb, c-Jun and Daxx. 6 Our previous studies have shown that genotoxic stressors such as camptothecin (CPT) and etoposide enhance g-secretase activity and Ab generation, 7,8 suggesting that modulation of g-secretase activity is a component of the genotoxic cell death pathway. As presenilin (PS) contains the core catalytic activity within the g-secretase complex, we hypothesized that PS has a key role in mediating...

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Section: Discussionsupporting

confidence: 80%

Critical role of presenilin-dependent γ-secretase activity in DNA damage-induced promyelocytic leukemia protein expression and apoptosis

et al. 2013

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“…Cyclin D1, which is expressed in very small amounts in terminally differentiated neurons, is elevated in response to neurotoxic stimuli, contributing to the process of CRNA (12,18). In addition, cyclin D1 is aberrantly expressed in patients with mild cognitive impairment and AD (11).…”

Section: Resultsmentioning

confidence: 99%

“…In response to neurotoxic insults like amyloid peptide A␤ 42 , the aberrant expression of cell cycle proteins like cyclins facilitates cell cycle reentry (15)(16)(17). In this context, cyclin D1 seems to play an important role in cell cycle-related neuronal apoptosis (CRNA), as its increased expression by A␤ 42 or DNA-damaging agents triggers this process (12,16,18). In addition, cyclin D1 is highly expressed in neurons of patients with mild cognitive impairment (MCI) and AD, which undergo CRNA (11).…”

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confidence: 99%

Regulation of Neuronal Cell Cycle and Apoptosis by MicroRNA 34a

Modi

Jaiswal

Sharma

2016

Molecular and Cellular Biology

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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...

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“…To detect SH-SY5Y cells in S phase of the cell cycle, 10 μM of 5′-bromo-2′-doxyuridine (BrdU, Sigma) was added to the culture medium for 2 h 30 min, cells fixed, and assessed for BrdU incorporation as previously described (Malik et al 2008). Nuclei were counterstained with Hoechst 33,342 (Invitrogen) to assay for total cell numbers.…”

Section: Brdu Incorporation Assaymentioning

confidence: 99%

Caffeine Modulates Tau Phosphorylation and Affects Akt Signaling in Postmitotic Neurons

et al. 2010

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Neuronal cell cycle reentry, which is associated with aberrant tau phosphorylation, is thought to be a mechanism of neurodegeneration in AD. Caffeine is a neuroprotective drug known to inhibit the cell cycle, suggesting that its neuroprotective nature may rely, at least in part, on preventing tau abnormalities secondary to its inhibitory effect on neuronal cell cycle-related pathways. Accordingly, we have explored in the present study the impact of caffeine on cell cycle-linked parameters and tau phosphorylation patterns in an attempt to identify molecular clues to its neuroprotective effect. We show that caffeine blocks the cell cycle at G1 phase in neuroblastoma cells and leads to a decrease in tau phosphorylation; similarly, exposure of postmitotic neurons to caffeine led to changes in tau phosphorylation concomitantly with downregulation of Akt signaling. Taken together, our results show a unique impact of caffeine on tau phosphorylation and warrant further investigation to address whether caffeine may help prevent neuronal death by preventing tau abnormalities secondary to aberrant entry into the cell cycle.

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Loss of neuronal cell cycle control as a mechanism of neurodegeneration in the Presenilin-1 Alzheimer's disease brain

Cited by 60 publications

References 31 publications

Critical role of presenilin-dependent γ-secretase activity in DNA damage-induced promyelocytic leukemia protein expression and apoptosis

Critical role of presenilin-dependent γ-secretase activity in DNA damage-induced promyelocytic leukemia protein expression and apoptosis

Regulation of Neuronal Cell Cycle and Apoptosis by MicroRNA 34a

Caffeine Modulates Tau Phosphorylation and Affects Akt Signaling in Postmitotic Neurons

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