Presenilin-Dependent  -Secretase-Mediated Control of p53-Associated Cell Death in Alzheimer's Disease

Costa, Cristine Alves da; Sunyach, Claire; Pardossi‐Piquard, Raphaëlle; Sévalle, Jean; Vincent, Bruno; Boyer, Nicole; Kawarai, Toshitaka; Girardot, Nadège; George-Hyslop, Peter St; Checler, Frédéric

doi:10.1523/jneurosci.0651-06.2006

Cited by 154 publications

(166 citation statements)

References 63 publications

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“…We have examined the ability of p53 to modulate PrP c promoter transactivation and mRNA expression and we show that p53 acts as a transcriptional activator of PrP c by binding directly to the suspected promoter sequence. Furthermore, we previously established that the ␤-amyloid precursor protein (␤APP-intracellular domain amyloid intracellular domain (AICD) generated after presenilin-dependent ␥-secretasemediated cleavage of ␤APP behaves as a transcriptional activator of p53 (Alves da Costa et al, 2006). Here, we show that presenilins also control PrP c transcription in a presenilin-dependent manner by increasing AICD-induced p53 expression.…”

Section: Introductionmentioning

confidence: 74%

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p53-Dependent Transcriptional Control of Cellular Prion by Presenilins

Vincent¹,

Sunyach²,

Orzechowski³

et al. 2009

J. Neurosci.

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The presenilin-dependent ␥-secretase processing of the ␤-amyloid precursor protein (␤APP) conditions the length of the amyloid ␤ peptides (A␤) that accumulate in the senile plaques of Alzheimer's disease-affected brains. This, together with an additional presenilinmediated -secretase cleavage, generates intracellular ␤APP-derived fragments named amyloid intracellular domains (AICDs) that regulate the transcription of several genes. We establish that presenilins control the transcription of cellular prion protein (PrP c ) by a ␥-secretase inhibitor-sensitive and AICD-mediated process. We demonstrate that AICD-dependent control of PrP c involves the tumor suppressor p53. Thus, p53-deficiency abolishes the AICD-mediated control of PrP c transcription. Furthermore, we show that p53 directly binds to the PrP c promoter and increases its transactivation. Overall, our study unravels a transcriptional regulation of PrP c by the oncogene p53 that is directly driven by presenilin-dependent formation of AICD. Furthermore, it adds support to previous reports linking secretase activities involved in ␤APP metabolism to the physiology of PrP c .

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Section: Introductionmentioning

confidence: 74%

“…We have previously demonstrated that AICDs can positively control p53 at the transcriptional level (Alves da Costa et al, 2006). In silico examination of the PrP c promoter revealed a putative although incomplete p53-binding site (el-Deiry et al, 1992) (Fig.…”

Section: Aicd-mediated Regulation Of Prpmentioning

confidence: 93%

p53-Dependent Transcriptional Control of Cellular Prion by Presenilins

Vincent¹,

Sunyach²,

Orzechowski³

et al. 2009

J. Neurosci.

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“…In TIF-IA mutants, one of the earliest events triggered by nucleolar damage is the increased stabilization of the transcription factor p53, and we show that inhibition of p53 abrogated the cellular loss. Interestingly, the importance of p53 for neurodegeneration has been shown in Huntington's, Alzheimer's, and Parkinson's diseases (Bae et al, 2005;Alves da Costa et al, 2006;Nair et al, 2006). The question remains how p53 can relay its devastating function in neurons.…”

Section: Discussionmentioning

confidence: 99%

Nucleolar Disruption in Dopaminergic Neurons Leads to Oxidative Damage and Parkinsonism through Repression of Mammalian Target of Rapamycin Signaling

Rieker¹,

Engblom²,

Kreiner³

et al. 2011

J. Neurosci.

141

198

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The nucleolus represents an essential stress sensor for the cell. However, the molecular consequences of nucleolar damage and their possible link with neurodegenerative diseases remain to be elucidated. Here, we show that nucleolar damage is present in both genders in Parkinson's disease (PD) and in the pharmacological PD model induced by the neurotoxin 1,2,3,6-tetrahydro-1-methyl-4-phenylpyridine hydrochloride (MPTP). Mouse mutants with nucleolar disruption restricted to dopaminergic (DA) neurons show phenotypic alterations that resemble PD, such as progressive and differential loss of DA neurons and locomotor abnormalities. At the molecular level, nucleolar disruption results in increased p53 levels and downregulation of mammalian target of rapamycin (mTOR) activity, leading to mitochondrial dysfunction and increased oxidative stress, similar to PD. In turn, increased oxidative stress induced by MPTP causes mTOR and ribosomal RNA synthesis inhibition. Collectively, these observations suggest that the interplay between nucleolar dysfunction and increased oxidative stress, involving p53 and mTOR signaling, may constitute a destructive axis in experimental and sporadic PD.

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“…Generation of an excess amount of Aβ activates p53 and induces neurodegeneration [18]. p53-associated cell death in Alzheimer disease was dependent on presenilin [34]. However, on the other hand, overexpression of Aph-1 and Pen-2 reduced p53 expression and activity and suppressed apoptosis [35], and consistently, knockdown of Pen-2 resulted in p53-dependent apoptosis [36].…”

Section: Discussionmentioning

confidence: 99%

Stimulation of p53 Transactivation Ability by Nicastrin in Mouse Fibroblasts

et al. 2010

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Nicastrin (NCSTN), a component of the γ-secretase complex, is involved in the p53-dependent apoptosis of neurons, although its mechanism remains unclear. We analyzed the effects of NCSTN transfection on the transactivity of p53 in ras-NIH3T3 mouse fibroblasts with a luciferase assay. Luciferase activity was elevated after transfection, suggesting the stimulation of p53 transactivation ability. In addition, the protein levels of endogenous mouse p53 and transfected human p53 increased. The effects of NCSTN appeared to be independent of γ-secretase activity because it was not inhibited by the γ-secretase inhibitor DAPT. The functional domains of NCSTN were further examined with NCSTN deletion mutants. Activation of the p53-responsive promoter was completely diminished in a NCSTN mutant lacking the amino acid residues between 306 and 360. Since this domain is a γ-secretase-substrate-recognition site, the activation of p53 by NCSTN may be mediated by γ-secretase-substrate-like molecules.

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Presenilin-Dependent -Secretase-Mediated Control of p53-Associated Cell Death in Alzheimer's Disease

Cited by 154 publications

References 63 publications

p53-Dependent Transcriptional Control of Cellular Prion by Presenilins

p53-Dependent Transcriptional Control of Cellular Prion by Presenilins

Nucleolar Disruption in Dopaminergic Neurons Leads to Oxidative Damage and Parkinsonism through Repression of Mammalian Target of Rapamycin Signaling

Stimulation of p53 Transactivation Ability by Nicastrin in Mouse Fibroblasts

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