ER-stress-associated functional link between Parkin and DJ-1 via a transcriptional cascade involving the tumor suppressor p53 and the spliced X-box binding protein XBP-1.

Parkin and DJ-1 are two multi-functional proteins linked to autosomal recessive early-onset Parkinson's disease (PD) that have been shown to functionally interact by as-yet-unknown mechanisms. We have delineated the mechanisms by which parkin controls DJ-1. Parkin modulates DJ-1 transcription and protein levels via a signaling cascade involving p53 and the endoplasmic reticulum (ER)-stress-induced active X-box-binding protein-1S (XBP-1S). Parkin triggers the transcriptional repression of p53 while p53 downregulates DJ-1 protein and mRNA expressions. We show that parkin-mediated control of DJ-1 is fully p53-dependent. Furthermore, we establish that p53 lowers the protein and mRNA levels of XBP-1S. Accordingly, we show that parkin ultimately upregulates XBP-1 levels. Subsequently, XBP-1S physically interacts with the DJ-1 promoter, thereby enhancing its promoter trans-activation, mRNA levels and protein expression. This data was corroborated by the examination of DJ-1 in both parkin- and p53-null mice brains. This transcriptional cascade is abolished by pathogenic parkin mutations and is independent of its ubiquitin-ligase activity. Our data establish a parkin-dependent ER-stress-associated modulation of DJ-1 and identifies p53 and XBP-1 as two major actors acting downstream of parkin in this signaling cascade in cells and in vivo. This work provides a mechanistic explanation for the increase in the unfolded protein response observed in PD pathology, i.e. that it is due to a defect in parkin-associated control of DJ-1.

Parkin as a Molecular Bridge Linking Alzheimer's and Parkinson's Diseases?

Alzheimer's (AD) and Parkinson's (PD) diseases are two distinct age-related pathologies that are characterized by various common dysfunctions. They are referred to as proteinopathies characterized by ubiquitinated protein accumulation and aggregation. This accumulation is mainly due to altered lysosomal and proteasomal clearing processes and is generally accompanied by ER stress disturbance, autophagic and mitophagic defects, mitochondrial structure and function alterations and enhanced neuronal cell death. Genetic approaches aimed at identifying molecular triggers responsible for familial forms of AD or PD have helped to understand the etiology of their sporadic counterparts. It appears that several proteins thought to contribute to one of these pathologies are also likely to contribute to the other. One such protein is parkin (PK). Here, we will briefly describe anatomical lesions and genetic advances linked to AD and PD as well as the main cellular processes commonly affected in these pathologies. Further, we will focus on current studies suggesting that PK could well participate in AD and thereby act as a molecular bridge between these two pathologies. In particular, we will focus on the transcription factor function of PK and its newly described transcriptional targets that are directly related to AD- and PD-linked cellular defects.

Therapeutic potential of parkin as a tumor suppressor via transcriptional control of cyclins in glioblastoma cell and animal models.

Parkin (PK) is an E3-ligase harboring tumor suppressor properties that has been associated to various cancer types including glioblastoma (GBM). However, PK is also a transcription factor (TF), the contribution of which to GBM etiology remains to be established. Methods: The impact of PK on GBM cells proliferation was analyzed by real-time impedance measurement and flow cytometry. Cyclins A and B proteins, promoter activities and mRNA levels were measured by western blot, luciferase assay and quantitative real-time PCR. Protein-protein and protein-promoter interactions were performed by co-immunoprecipitation and by ChIP approaches. The contribution of endogenous PK to tumor progression in vivo was performed by allografts of GL261 GBM cells in wild-type and PK knockout mice. Results: We show that overexpressed and endogenous PK control GBM cells proliferation by modulating the S and G2/M phases of the cell cycle via the trans-repression of cyclin A and cyclin B genes. We establish that cyclin B is regulated by both E3-ligase and TF PK functions while cyclin A is exclusively regulated by PK TF function. PK invalidation leads to enhanced tumor progression in immunocompetent mice suggesting an impact of PK-dependent tumor environment to tumor development. We show that PK is secreted by neuronal cells and recaptured by tumor cells. Recaptured PK lowered cyclins levels and decreased GBM cells proliferation. Further, PK expression is decreased in human GBM biopsies and its expression is inversely correlated to both cyclins A and B expressions. Conclusion: Our work demonstrates that PK tumor suppressor function contributes to the control of tumor by its cellular environment. It also shows a key role of PK TF function in GBM development via the control of cyclins in vitro and in vivo. It suggests that therapeutic strategies aimed at controlling PK shuttling to the nucleus may prove useful to treat GBM.

Transcription- and phosphorylation-dependent control of a functional interplay between XBP1s and PINK1 governs mitophagy and potentially impacts Parkinson disease pathophysiology.

Parkinson disease (PD)-affected brains show consistent endoplasmic reticulum (ER) stress and mitophagic dysfunctions. The mechanisms underlying these perturbations and how they are directly linked remain a matter of questions. XBP1 is a transcription factor activated upon ER stress after unconventional splicing by the nuclease ERN1/IREα thereby yielding XBP1s, whereas PINK1 is a kinase considered as the sensor of mitochondrial physiology and a master gatekeeper of mitophagy process. We showed that XBP1s transactivates PINK1 in human cells, primary cultured neurons and mice brain, and triggered a pro-mitophagic phenotype that was fully dependent of endogenous PINK1. We also unraveled a PINK1-dependent phosphorylation of XBP1s that conditioned its nuclear localization and thereby, governed its transcriptional activity. PINK1-induced XBP1s phosphorylation occurred at residues reminiscent of, and correlated to, those phosphorylated in substantia nigra of sporadic PD-affected brains. Overall, our study delineated a functional loop between XBP1s and PINK1 governing mitophagy that was disrupted in PD condition.Abbreviations: 6OHDA: 6-hydroxydopamine; baf: bafilomycin A1; BECN1: beclin 1; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CASP3: caspase 3; CCCP: carbonyl cyanide chlorophenylhydrazone; COX8A: cytochrome c oxidase subunit 8A; DDIT3/CHOP: DNA damage inducible transcript 3; EGFP: enhanced green fluorescent protein; ER: endoplasmic reticulum; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; FACS: fluorescence-activated cell sorting; HSPD1/HSP60: heat shock protein family D (Hsp60) member 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFN2: mitofusin 2; OPTN: optineurin; PD: Parkinson disease; PINK1: PTEN-induced kinase 1; PCR: polymerase chain reaction:; PRKN: parkin RBR E3 ubiquitin protein ligase; XBP1s [p-S61A]: XBP1s phosphorylated at serine 61; XBP1s [p-T48A]: XBP1s phosphorylated at threonine 48; shRNA: short hairpin RNA, SQSTM1/p62: sequestosome 1; TIMM23: translocase of inner mitochondrial membrane 23; TM: tunicamycin; TMRM: tetramethyl rhodamine methylester; TOMM20: translocase of outer mitochondrial membrane 20; Toy: toyocamycin; TP: thapsigargin; UB: ubiquitin; UB (S65): ubiquitin phosphorylated at serine 65; UPR: unfolded protein response, XBP1: X-box binding protein 1; XBP1s: spliced X-box binding protein 1.

p53 is regulated by and regulates members of the gamma-secretase complex.

Amyloid beta-peptides is the generic term for a set of hydrophobic peptides that accumulate in Alzheimer's disease (AD)-affected brains. These amyloid-beta peptide fragments are mainly generated by an enzymatic machinery referred to as gamma-secretase complex that is built up by the association of four distinct proteins, namely presenilin 1 (PS1) or PS2, nicastrin, Aph-1 and Pen-2. AD is also characterized by exacerbated cell death that appears linked to the tumor suppressor p53. Interestingly, all members of the gamma-secretase complex control p53-dependent cell death. On the other hand, p53 appears to be able to regulate directly or indirectly the expression and transcription of PS1, PS2 and Pen-2. This review will focus on the functional cross-talk between the members of the gamma-secretase complex and p53 and will discuss the putative implication of this oncogene in AD pathology.

Presenilin-dependent transcriptional control of the Abeta-degrading enzyme neprilysin by intracellular domains of betaAPP and APLP.

Amyloid beta-peptide (Abeta), which plays a central role in Alzheimer's disease, is generated by presenilin-dependent gamma-secretase cleavage of beta-amyloid precursor protein (betaAPP). We report that the presenilins (PS1 and PS2) also regulate Abeta degradation. Presenilin-deficient cells fail to degrade Abeta and have drastic reductions in the transcription, expression, and activity of neprilysin, a key Abeta-degrading enzyme. Neprilysin activity and expression are also lowered by gamma-secretase inhibitors and by PS1/PS2 deficiency in mouse brain. Neprilysin activity is restored by transient expression of PS1 or PS2 and by expression of the amyloid intracellular domain (AICD), which is cogenerated with Abeta, during gamma-secretase cleavage of betaAPP. Neprilysin gene promoters are transactivated by AICDs from APP-like proteins (APP, APLP1, and APLP2), but not by Abeta or by the gamma-secretase cleavage products of Notch, N- or E- cadherins. The presenilin-dependent regulation of neprilysin, mediated by AICDs, provides a physiological means to modulate Abeta levels with varying levels of gamma-secretase activity.

p53-dependent control of cell death by nicastrin: lack of requirement for presenilin-dependent gamma-secretase complex.

Nicastrin (NCT) is a component of the presenilin (PS)-dependent gamma-secretase complexes that liberate amyloid beta-peptides from the beta-Amyloid Precursor Protein. Several lines of evidence indicate that the members of these complexes could also contribute to the control of cell death. Here we show that over-expression of NCT increases the viability of human embryonic kidney (HEK293) cells and decreases staurosporine (STS)- and thapsigargin (TPS)-induced caspase-3 activation in various cell lines from human and neuronal origins by Akt-dependent pathway. NCT lowers p53 expression, transcriptional activity and promoter transactivation and reduces p53 phosphorylation. NCT-associated protection against STS-stimulated cell death was completely abolished by p53 deficiency. Conversely, the depletion of NCT drastically enhances STS-induced caspase-3 activation and p53 pathway and favored p53 nuclear translocation. We examined whether NCT protective function depends on PS-dependent gamma-secretase activity. First, a 29-amino acid deletion known to reduce NCT-dependent amyloid beta-peptide production did not affect NCT-associated protective phenotype. Second, NCT still reduces STS-induced caspase-3 activation in fibroblasts lacking PS1 and PS2. Third, the gamma-secretase inhibitor DFK167 did not affect NCT-mediated reduction of p53 activity. Altogether, our study indicates that NCT controls cell death via phosphoinositide 3-kinase/Akt and p53-dependent pathways and that this function remains independent of the activity and molecular integrity of the gamma-secretase complexes.

Upregulation of the Sarco-Endoplasmic Reticulum Calcium ATPase 1 Truncated Isoform Plays a Pathogenic Role in Alzheimer's Disease.

Dysregulation of the Endoplasmic Reticulum (ER) Ca2+ homeostasis and subsequent ER stress activation occur in Alzheimer Disease (AD). We studied the contribution of the human truncated isoform of the sarco-endoplasmic reticulum Ca2+ ATPase 1 (S1T) to AD. We examined S1T expression in human AD-affected brains and its functional consequences in cellular and transgenic mice AD models. S1T expression is increased in sporadic AD brains and correlates with amyloid ß (Aß) and ER stress chaperone protein levels. Increased S1T expression was also observed in human neuroblastoma cells expressing Swedish-mutated ß-amyloid precursor protein (ßAPP) or treated with Aß oligomers. Lentiviral overexpression of S1T enhances in return the production of APP C-terminal fragments and Aß through specific increases of ß-secretase expression and activity, and triggers neuroinflammation. We describe a molecular interplay between S1T-dependent ER Ca2+ leak, ER stress and ßAPP-derived fragments that could contribute to AD setting and/or progression.

Nuclear TP53: An unraveled function as transcriptional repressor of PINK1.

The tumor suppressor TP53/p53 is a key protein in both neurodegenerative diseases and cancer. Thus, TP53-linked cell death appears exacerbated in several age-related neuropathologies, while TP53 mutation-associated phenotypes indicate a loss of function accounting for approximately half of cancers. Thus, TP53 plays a pivotal role in these phenotypically distinct pathologies, a hypothesis reinforced by recent epidemiological studies suggesting an opposite risk to develop one type of pathology relative to the other. Dysfunctions in mitophagic processes also occur in both types of pathologies and again, TP53 has been proposed as one of the regulators of this cellular process. The consensus view postulates that TP53 exerts both anti- and pro-autophagy functions that are directly driven by a specific subcellular localization. Thus, TP53 positively modulates autophagy via the transcriptional control of several genes while it is acknowledged that its anti-autophagy phenotype is exclusively linked to a transcription-independent cytosolic control of an AMPK-MTOR cascade. Our study indicates that TP53 can also downregulate the specialized autophagy-related mitophagy response via the transcriptional repression of PINK1. This is the first demonstration of an anti-mitophagic control by nuclear TP53.

The Transcription Factor Function of Parkin: Breaking the Dogma.

PRKN (PARK2) is a key gene involved in both familial and sporadic Parkinson's disease that encodes parkin (PK). Since its discovery by the end of the 90s, both functional and more recently, structural studies led to a consensual view of PK as an E3 ligase only. It is generally considered that this function conditions the cellular load of a subset of cytosolic proteins prone to proteasomal degradation and that a loss of E3 ligase function triggers an accumulation of potentially toxic substrates and, consequently, a neuronal loss. Furthermore, PK molecular interplay with PTEN-induced kinase 1 (PINK1), a serine threonine kinase also involved in recessive cases of Parkinson's disease, is considered to underlie the mitophagy process. Thus, since mitochondrial homeostasis significantly governs cell health, there is a huge interest of the scientific community centered on PK function. In 2009, we have demonstrated that PK could also act as a transcription factor (TF) and induces neuroprotection via the downregulation of the pro-apoptotic and tumor suppressor factor, p53. Importantly, the DNA-binding properties of PK and its nuclear localization suggested an important role in the control of several genes. The duality of PK subcellular localization and of its associated ubiquitin ligase and TF functions suggests that PK could behave as a key molecular modulator of various physiological cellular signaling pathways that could be disrupted in pathological contexts. Here, we update the current knowledge on PK direct and indirect TF-mediated control of gene expression.

Nuclear p53-mediated repression of autophagy involves PINK1 transcriptional down-regulation.

p53 is a transcription factor that is implicated in the control of both apoptotic and autophagic cell death. This tumor suppressor elicits both pro-autophagic and anti-autophagic phenotypes depending of its intracellular localization. The ability of p53 to repress autophagy has been exclusively associated to its cytoplasmic localization. Here, we show that transcriptional activity of p53 also contributes to autophagy down-regulation. Thus, nuclear p53 controls PINK1, a key protein involved in the control of mitophagy, by repressing its promoter activity, protein and mRNA levels, ex-vivo and in vivo. We establish that deletion of an identified p53 responsive element on PINK1 promoter impacts p53-mediated PINK1 transcriptional repression and we demonstrate a p53-PINK1 physical interaction by chromatin immunoprecipitation. Accordingly, we show that only nuclear p53 accounts for its ability to repress PINK1 gene transcription. Further, we demonstrate ex-vivo and in vivo that p53 invalidation in human cells increases LC3 maturation as well as optineurin and NDP52 autophagy receptors expression and down-regulates TIM23, TOM20 and HSP60 mitophagy markers. Importantly, this phenotype is mimicked by TP53 invalidation in mice brain. Finally, by combining pharmacological and genetic approaches, we show that the p53-mediated negative regulation of autophagy is PINK1-dependent. Thus pifithrin-α-mediated blockade of p53 transcriptional activity enhances LC3 maturation and reduces p62, TIM23, TOM20 and HSP60 protein levels. This pifithrin-α-associated pro-mitophagy phenotype is fully abolished by PINK1 depletion. This data unravels a novel pathway by which nuclear p53 can repress autophagy/mitophagy that could underlie important dysfunctions in both neurodegenerative and cancer diseases.

ß-Amyloid Precursor Protein Intracellular Domain Controls Mitochondrial Function by Modulating Phosphatase and Tensin Homolog-Induced Kinase 1 Transcription in Cells and in Alzheimer Mice Models.

BACKGROUND: Mitophagy and mitochondrial dynamics alterations are two major hallmarks of neurodegenerative diseases. Dysfunctional mitochondria accumulate in Alzheimer's disease-affected brains by yet unexplained mechanisms. METHODS: We combined cell biology, molecular biology, and pharmacological approaches to unravel a novel molecular pathway by which presenilins control phosphatase and tensin homolog-induced kinase 1 (Pink-1) expression and transcription. In vivo approaches were carried out on various transgenic and knockout animals as well as in adeno-associated virus-infected mice. Functional readout and mitochondrial physiology (mitochondrial potential) were assessed by combined procedures including flow cytometry, live imaging analysis, and immunohistochemistry. RESULTS: We show that presenilins 1 and 2 trigger opposite effects on promoter transactivation, messenger RNA, and protein expression of Pink-1. This control is linked to γ-secretase activity and ß-amyloid precursor protein but is independent of phosphatase and tensin homolog. We show that amyloid precursor protein intracellular domain (AICD) accounts for presenilin-dependent phenotype and upregulates Pink-1 transactivation in cells as well as in vivo in a Forkhead box O3a-dependent manner. Interestingly, the modulation of γ-secretase activity or AICD expression affects Pink-1-related control of mitophagy and mitochondrial dynamics. Finally, we show that parkin acts upstream of presenilins to control Pink-1 promoter transactivation and protein expression. CONCLUSIONS: Overall, we delineate a molecular cascade presenilins-AICD-Forkhead box O3a linking parkin to Pink-1. Our study demonstrates AICD-mediated Pink-1-dependent control of mitochondrial physiology by presenilins. Furthermore, it unravels a parkin-Pink-1 feedback loop controlling mitochondrial physiology that could be disrupted in neurodegenerative conditions.

Presenilin-dependent gamma-secretase-mediated control of p53-associated cell death in Alzheimer's disease.

Presenilins (PSs) are part of the gamma-secretase complex that produces the amyloid beta-peptide (Abeta) from its precursor [beta-amyloid precursor protein (betaAPP)]. Mutations in PS that cause familial Alzheimer's disease (FAD) increase Abeta production and trigger p53-dependent cell death. We demonstrate that PS deficiency, catalytically inactive PS mutants, gamma-secretase inhibitors, and betaAPP 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 betaAPP-deficient mice. The gamma- and epsilon-secretase-derived amyloid intracellular C-terminal domain (AICD) fragments (AICDC59 and AICDC50, respectively) of betaAPP 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.

Catabolism of endogenous and overexpressed APH1a and PEN2: evidence for artifactual involvement of the proteasome in the degradation of overexpressed proteins.

PS (presenilin)-dependent gamma-secretase occurs as a high-molecular-mass complex composed of either PS1 or PS2 associated with Nct (nicastrin), PEN2 (presenilin enhancer 2 homologue) and APH1 (anterior pharynx defective 1 homologue). Numerous reports have documented the very complicated physical and functional cross-talk between these proteins that ultimately governs the biological activity of the gamma-secretase, but very few studies examined the fate of the components of the complex. We show that, in both HEK-293 cells and the TSM1 neuronal cell line, the immunoreactivities of overexpressed myc-tagged-APH1a and -PEN2 were enhanced by the proteasome inhibitors ZIE and lactacystin, whereas a broad range of protease inhibitors had no effect. By contrast, proteasome inhibitors were totally unable to affect the cellular expression of endogenous APH1aL and PEN2 in HEK-293 cells, TSM1 and primary cultured cortical neurons. To explain this apparent discrepancy, we examined the degradation of myc-tagged-APH1a and -PEN2, in vitro, by cell extracts containing endogenous proteasome and by purified 20S proteasome. Strikingly, myc-tagged-APH1a and -PEN2 resist proteolysis by endogenous proteasome and purified 20S proteasome. We also show that endogenous PEN2 expression was drastically higher in wild-type than in PS- and Nct-deficient fibroblasts and was enhanced by proteasome inhibitors only in the two deficient cell systems. However, here again, purified 20S proteasome appeared unable to cleave endogenous PEN2 present in PS-deficient fibroblasts. The levels of endogenous APH1aL-like immunoreactivity were not modified by proteasome inhibitors and were unaffected by PS deficiency. Altogether, our results indicate that endogenous PEN2 and APH1aL do not undergo proteasomal degradation under physiological conditions in HEK-293 cells, TSM1 cells and fibroblasts and that the clearance of PEN2 in PS- and Nct-deficient fibroblasts is not mediated by 20S proteasome. Whether the 26S proteasome participates to PEN2 proteolysis in deficient fibroblasts remains to be established.

Presenilins at the crossroad of a functional interplay between PARK2/PARKIN and PINK1 to control mitophagy: Implication for neurodegenerative diseases.

Autophagic and mitophagic defects are consistently observed in Alzheimer's disease-affected brains. However, the mechanistic defects underlying these anatomical lesions remained unexplained. We have delineated a molecular cascade by which PSEN1 and PSEN2 (presenilins 1 and 2) control PINK1 transcription and function by an AICD-mediated FOXO3a-dependent mechanism. Further, we establish that PARK2 (parkin) acts upstream to PINK1 and regulates its function by a PSEN-dependent mechanism. Our study thus demonstrates a functional interplay between PSEN and PINK1 and establishes a feedback process by which PARK2 and PINK1 could control mitochondrial dysfunction and autophagic processes in various neurodegenerative pathologies including Alzheimer's and Parkinson's diseases.

Direct α-synuclein promoter transactivation by the tumor suppressor p53.

BACKGROUND: Parkinson's disease (PD) is a motor disease associated with the degeneration of dopaminergic neurons of the substantia nigra pars compacta. p53 is a major neuronal pro-apoptotic factor that is at the center of gravity of multiple physiological and pathological cascades, some of which implying several key PD-linked proteins. Since p53 is up-regulated in PD-affected brain, we have examined its ability to regulate the transcription of α-synuclein, a key protein that accumulates in PD-related Lewy bodies. RESULTS: We show that pharmacological and genetic up-regulation of p53 expression lead to a strong increase of α-synuclein protein, promoter activity and mRNA levels. Several lines of evidence indicate that this transcriptional control is due to the DNA-binding properties of p53. Firstly, p53 DNA-binding dead mutations abolish p53 regulation of α-synuclein. Secondly, the deletion of p53 responsive element from α-synuclein promoter abrogates p53-mediated α-synuclein regulation. Thirdly, gel shift and chromatin immunoprecipitation studies indicate that p53 interacts physically with α-synuclein promoter both in vitro and in a physiological context. Furthermore, we show that the depletion of endogenous p53 in cells as well as in knockout mice down-regulates α-synuclein transcription. CONCLUSIONS: Overall, we have identified α-synuclein as a new transcriptional target of p53 and delineated a cellular mechanism feeding the accumulation of toxic aggregated α-synuclein in PD. This original α-syn regulatory mechanism may be central to PD-related cell death and may lead to novel opportunities to design alternative neuroprotective strategies in PD.

JLK inhibitors: isocoumarin compounds as putative probes to selectively target the gamma-secretase pathway.

Alzheimer's disease is characterized by the extracellular deposition of the amyloid beta-peptide that derives from its precursor betaAPP by sequential actions of beta- and gamma- secretases, respectively. Recent studies aimed at identifying these enzymes have been reported as it is thougth that their inhibition should hopefully lead to reduce Abeta load in the AD brains. beta-secretase seems to be due to BACE1, a novel membrane-bound aspartyl protease. gamma-secretase identification is still a matter of controversy. Invalidation of presenilin genes was reported to impair both gamma-secretase-mediated Abeta production and Notch cleavage leading to NICD production. This observation together with another biochemical and pharmacological evidences led to suggest that presenilins could be the genuine long-searched gamma-secretase that would be responsible for both APP and Notch cleavages. We have designed novel non peptidic potential inhibitors of gamma-secretase (referred to as JLK inhibitors) and examined their ability to prevent Abeta40 and Abeta42 secretions as well as NICD production. Three out of a series of these agents drastically lower the recoveries of both Abeta40 and Abeta42 produced by betaAPP-expressing cell lines and concomitantly protect intracellular C99 and C83 recoveries. These inhibitors also prevent Abeta40/42 productions by C99-expressing cells. Interestingly, these inhibitors were totally unable to affect the DeltaENotch cleavage leading to NICD generation. Here, we also further characterize the pharmacological properties and specificity of these JLK inhibitors.

p53 in neurodegenerative diseases and brain cancers.

More than thirty years elapsed since a protein, not yet called p53 at the time, was detected to bind SV40 during viral infection. Thousands of papers later, p53 evolved as the main tumor suppressor involved in growth arrest and apoptosis. A lot has been done but the protein has not yet revealed all its secrets. Particularly important is the observation that in totally distinct pathologies where apoptosis is either exacerbated or impaired, p53 appears to play a central role. This is exemplified for Alzheimer's and Parkinson's diseases that represent the two main causes of age-related neurodegenerative affections, where cell death enhancement appears as one of the main etiological paradigms. Conversely, in cancers, about half of the cases are linked to mutations in p53 leading to the impairment of p53-dependent apoptosis. The involvement of p53 in these pathologies has driven a huge amount of studies aimed at designing chemical tools or biological approaches to rescue p53 defects or over-activity. Here, we describe the data linking p53 to neurodegenerative diseases and brain cancers, and we document the various strategies to interfere with p53 dysfunctions in these disorders.

Apoptosis in Parkinson's disease: is p53 the missing link between genetic and sporadic Parkinsonism?

Parkinson's disease (PD) is a major age-related neurodegenerative disorder characterized by a massive and specific loss of dopaminergic neurons of the substantia nigra pars compacta. The cellular alterations are clinically translated into an invalidating movement disability associated to three canonical symptoms that are bradykinesia, resting tremor and rigidity. The exact causes of this neuronal loss are unknown, but a network of evidences indicates a major contribution of orchestrated cell death processes, also known as apoptosis. Apoptotic cell death is a normal process, the alteration of which triggers several pathologies including cancer and neurodegenerative disorders. Exhaustive work has been done to delineate the cellular mechanisms responsible for the exacerbated cell death of dopaminergic neurons observed in PD. Overall, the oncogene p53 has been identified as a key effector protein. This review will focus on the clues linking p53 to the etiology of PD and the evidences that this protein may be at the center of multiple signaling cascades not only altered by mutations of various proteins responsible for familial cases of PD but also on more general sporadic cases of this devastating disease.