Wild-type and mutated presenilins 2 trigger p53-dependent apoptosis and down-regulate presenilin 1 expression in HEK293 human cells and in murine neurons

Costa, Cristine Alves da; Paitel, Erwan; Mattson, Mark P.; Amson, Robert; Telerman, Adam; Ancolio, Karine; Checler, Frédéric

doi:10.1073/pnas.062059899

Cited by 127 publications

(128 citation statements)

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“…Furthermore, primary cultured hippocampal neurons prepared from mice harboring mutant PS1 exhibit increased vulnerability to apoptosis and activated caspase (Guo et al, 1999). Several studies have shown that mutations in PS2 enhance susceptibility to cell death (Wolozin et al, 1996;Alves da Costa et al, 2002), likely via a p53-dependent mechanism (Alves da Costa et al, 2002). However, it is presently unclear whether this neuronal death is simply a direct consequence of the accumulation of neurotoxic A␤ or whether cell death also occurs because other signaling pathways are perturbed as well.…”

Section: Introductionmentioning

confidence: 95%

“…Cellular p53 immunoreactivity was analyzed by Western blot, using a 1:10,000 dilution of an anti-p53 mouse monoclonal antibody (Santa Cruz Biotechnology, Santa Cruz, CA) in nuclear extracts prepared as previously described for cytochrome c translocation experiments (Alves da Costa et al, 2002) while murine brain p53 was analyzed in total homogenates, using the conditions described above. The activity of p53 was measured after transient transfection of the PG13-luciferase (PG13) cDNA kindly provided by Dr. B. Vogelstein (Baltimore, MD).…”

Section: Methodsmentioning

confidence: 99%

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

Costa

Sunyach

Pardossi‐Piquard

et al. 2006

Journal of Neuroscience

152

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Presenilins (PSs) are part of the ␥-secretase complex that produces the amyloid ␤-peptide (A␤) from its precursor [␤-amyloid precursor protein (␤APP)]. Mutations in PS that cause familial Alzheimer's disease (FAD) increase A␤ production and trigger p53-dependent cell death. We demonstrate that PS deficiency, catalytically inactive PS mutants, ␥-secretase inhibitors, and ␤APP or amyloid precursor protein-like protein 2 (APLP2) depletion all reduce the expression and activity of p53 and lower the transactivation of its promoter and mRNA expression. p53 expression also is diminished in the brains of PS-or ␤APP-deficient mice. The ␥-and -secretase-derived amyloid intracellular C-terminal domain (AICD) fragments (AICDC59 and AICDC50, respectively) of ␤APP trigger p53-dependent cell death and increase p53 activity and mRNA. Finally, PS1 mutations enhance p53 activity in human embryonic kidney 293 cells and p53 expression in FAD-affected brains. Thus our study shows that AICDs control p53 at a transcriptional level, in vitro and in vivo, and that FAD mutations increase p53 expression and activity in cells and human brains.

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Section: Introductionmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

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

Costa

Sunyach

Pardossi‐Piquard

et al. 2006

Journal of Neuroscience

152

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“…6,7,11,[30][31][32][33][34] In addition, studies that included these essential control experiments often used cells expressing either a non-functional p53 mutant or a p53 protein that is inactivated by the papilloma virus E6 protein. 12,34,35 The inability, shown herein, of PFT-a to protect these cells from apoptosis might, however, be because of a competitive Figure 6 PFT-a prevents hyperphosphorylation of pRb, but does not mediate its protective effect through this tumor suppressor.…”

Section: Discussionmentioning

confidence: 99%

Pifithrin-α protects against DNA damage-induced apoptosis downstream of mitochondria independent of p53

et al. 2009

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Pifithrin-a (PFT-a) was shown to specifically block transcriptional activity of the tumor suppressor p53 and was therefore proposed to be useful in preventing the severe side effects often associated with chemo-and radiotherapy. We report here that although PFT-a efficiently protected different cell types from DNA damage-induced apoptosis, it mediated this effect regardless of the presence or absence of p53. Interestingly, PFT-a blocked the apoptosome-mediated processing and activation of caspase-9 and -3 without interfering with the activation of mitochondria. Neither the DNA damage-induced activation of Bax or Bak nor the loss of the mitochondrial membrane potential or the final release of cytochrome c were inhibited by this compound. Instead, the ability of PFT-a to protect p53-deficient cells from DNA damage-induced caspase activation and apoptosis was greatly diminished after siRNA-mediated downregulation of cyclin-D1 expression. In contrast, downregulation of other proteins involved in cell-cycle progression, such as the retinoblastoma protein, cyclin D3, as well as the cyclin-dependent kinases, 2, 4 and 6, could not abolish this protection. Thus, our data show that PFT-a protects cells from DNA damage-induced apoptosis also by a p53-independent mechanism that takes place downstream of mitochondria and that might involve cyclin D1.

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“…This strategy could perhaps be extrapolated to other neurodegenerative diseases. Thus, we previously established that presenilin 2, its mutated counterpart (48), and its C-terminal fragment (49) trigger a pro-apoptotic phenotype that could, to some extent, account for some of the neuropathological stigmata observed in Alzheimer's disease (50,51). Amazingly, in prion-related diseases we also recently showed that overexpression of PrP c led to a drastic Mdm2-regulated, p53-dependent caspase 3 activation (29).…”

Section: ␤-Synuclein Protects Neurons From Caspase 3 Activationmentioning

confidence: 99%

β-Synuclein Displays an Antiapoptotic p53-dependent Phenotype and Protects Neurons from 6-Hydroxydopamine-induced Caspase 3 Activation

Costa

Masliah

Checler

2003

Journal of Biological Chemistry

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We have established stable transfectants expressing ␤-synuclein in TSM1 neurons. We show that in basal and staurosporine-induced conditions the number of terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling (TUNEL)-positive ␤-synuclein-expressing neurons was drastically lower than in mock-transfected TSM1 cells. This was accompanied by a lower DNA fragmentation as evidenced by the reduction of propidium iodide incorporation measured by fluorescence-activated cell sorter analysis. ␤-Synuclein strongly reduces staurosporine-induced caspase 3 activity and immunoreactivity. We establish that ␤-synuclein triggers a drastic reduction of p53 expression and transcriptional activity. This was accompanied by increased Mdm2 immunoreactivity while p38 expression appeared enhanced, indicating that ␤-synuclein-induced p53 downregulation likely occurs at a post-transcriptional level. We showed previously that ␣-synuclein displays an antiapoptotic function that was abolished by the dopaminergic derived toxin 6-hydroxydopamine (6OHDA). Interestingly, ␤-synuclein retains its ability to protect TSM1 neurons even after 6OHDA treatment. Furthermore, ␤-synuclein restores the antiapoptotic function of ␣-synuclein in 6OHDA-treated neurons. Altogether, our data document for the first time that ␤-synuclein protects neurons from staurosporine and 6OHDA-stimulated caspase activation in a p53-dependent manner. Our observation that ␤-synuclein contributes to restoration of the ␣-synuclein antiapoptotic function abolished by 6OHDA may have direct implications for Parkinson's disease pathology. In this context, the cross-talk between these two parent proteins is discussed.Parkinson's disease (PD) 1 is one of the most common and devastating diseases in the elderly (1, 2). This pathology is characterized by intracellular aggregates, called Lewy bodies (LB) (3, 4) that are thought to be responsible for final dementia occurring not only in PD but also in Lewy body diseases. The main component of LB was identified as ␣-synuclein (5), a 140-amino acid-long synaptic protein (6) that accumulates within these neuropathological hallmarks (7-9). The central role of ␣-synuclein in PD pathology has been emphasized by the observation that familial forms of PD were due to two mutations borne by ␣-synuclein (10, 11). Interestingly, these mutations trigger alterations of the biophysical properties of ␣-synuclein, leading to an exacerbation of misfolding and aggregation (12). Therefore, as with many other neurodegenerative diseases such as Alzheimer's and prion diseases, among others (13-15), PD can be documented as a disease associated with protein misfolding. The fact that such aggregates of proteins were recently shown to exhibit an intrinsic toxic potential (16) could lead to a reunifying theory linking misfolding and neurodegeneration.Interestingly, we have shown that ␣-synuclein displays an antiapoptotic phenotype that was abolished by PD-related mutations (17). This antiapoptotic function was also prevented when neuronal cells were expo...

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Wild-type and mutated presenilins 2 trigger p53-dependent apoptosis and down-regulate presenilin 1 expression in HEK293 human cells and in murine neurons

Cited by 127 publications

References 51 publications

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

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

Pifithrin-α protects against DNA damage-induced apoptosis downstream of mitochondria independent of p53

β-Synuclein Displays an Antiapoptotic p53-dependent Phenotype and Protects Neurons from 6-Hydroxydopamine-induced Caspase 3 Activation

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