p53 in neurodegenerative diseases and brain cancers.

Pharmacology & Therapeutics 142 (2014) 99–113

Contents lists available at ScienceDirect

Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera

Associate editor: M. Mouradian

p53 in neurodegenerative diseases and brain cancers Frédéric Checler ⁎, Cristine Alves da Costa ⁎⁎ Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275 CNRS/UNS, “Labex Distalz”, 660 route des Lucioles, 06560, Sophia-Antipolis, Valbonne, France

a r t i c l e

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a b s t r a c t 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. © 2013 Elsevier Inc. All rights reserved.

Keywords: p53 Signaling Alzheimer's disease Parkinson's disease Cerebral cancers Therapeutics

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . 2. p53 and Alzheimer's disease . . . . . . . . . . . . . . 3. p53 and Parkinson's disease . . . . . . . . . . . . . . 4. p53 and prions . . . . . . . . . . . . . . . . . . . . 5. p53 and brain cancers . . . . . . . . . . . . . . . . 6. Pharmacological and gene therapy strategies targeting p53 7. Concluding remarks . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The first report on the presence of a previously unknown protein, the expression of which increased upon SV40 infection, came out over thirty years ago (Lane & Crawford, 1979; Linzer & Levine, 1979). Indeed, a 53 kDa phosphoprotein was consistently detected in a wide series of human tumor cells (Crawford, Pim, Gurney, Goodfellow, & TaylorPapadimitriou, 1981). Interestingly, this protein that was baptized p53 and that is currently recognized as the most famous tumor suppressor ⁎ Corresponding author. Tel.: +33 4 93953460; fax: +33 4 93953408. ⁎⁎ Corresponding author. Tel.: +33 4 93953457; fax: +33 4 93953408. E-mail addresses: [email protected] (F. Checler), [email protected] (C. Alves da Costa). 0163-7258/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pharmthera.2013.11.009

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was first considered as an oncogene. Thus, the over-expression of p53 cDNA isolated from p53 clonal cells was highly tumorigenic and could transform embryonic cells (Eliyahu, Michalovitz, & Oren, 1985; Eliyahu, Raz, Gruss, Givol, & Oren, 1984). It appeared later that the isolated clones harbored a mutated p53, while wild-type p53 prevented oncogene-induced cell transformation (Finlay, Hinds, & Levine, 1989). These observations indicated that p53 likely behaved as a tumor suppressor in a normal context, and that p53 function could have been impaired by mutations. Obviously, the possibility that such dysfunction could wholly account for, or contribute to, cancer onset and/or progression was rapidly the center of a huge amount of research. Several lines of data supported this view but the likely most convincing evidence came from the demonstration that p53 knockout mice develop tumors very early (Donehower et al., 1992), and that about 50% of human cancers

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were associated with p53 mutations on both alleles of the gene (Olivier, Hollstein, & Hainaut, 2010; Robles & Harris, 2010). Subsequently, p53 was shown to behave as a transcription factor (el-Deiry, Kern, Pietenpol, Kinzler, & Vogelstein, 1992; Funk, Pak, Karas, Wright, & Shay, 1992) able to modulate a series of genes, the list of which is still increasing today. Notably, p53 regulates several genes involved in cell cycle control and apoptotic pathways (Beckerman & Prives, 2010), and its main function is in arresting cell cycle and promoting apoptosis. In this context, it makes sense to envision that a p53 defect could trigger cell transformation and cancer. When it became apparent later that apoptosis exacerbation is a characteristic of several neurodegenerative diseases, p53 came on stage in research concerning several of these neurological disorders. This review will focus particularly on the contribution of p53 in brain cancers and in Alzheimer's, Parkinson's and prion diseases, although p53 is involved in several types of cancers (Lane & Levine, 2010; Olivier et al., 2010; Robles & Harris, 2010) and implicated in other neurodegenerative disorders such as Huntington's disease (Bae et al., 2005; Burton, 2005; Feng et al., 2006).

2. p53 and Alzheimer's disease Alzheimer's disease (AD) is the most frequent age-related neurodegenerative disease (Hebert, Weuve, Scherr, & Evans, 2013; Holtzman, Mandelkow, & Selkoe, 2012; Prestia et al., 2013). Its pathology is characterized by two main histological lesions, the senile plaques and the neurofibrillary tangles (Selkoe, 1991; Suh & Checler, 2002). Tangles (Spillantini & Goedert, 1998) are essentially due to the intracellular accumulation of hyperphosphorylated tau protein (Buee et al., 2010; Mandelkow, 1999), while senile plaques are extracellular deposits mainly due to the aggregation of a set of various hydrophobic peptides semantically gathered under the term of amyloid-β (Αβ) peptides (Glenner & Wong, 1984; Masters et al., 1985). Canonical Aβ consists of 40–42 amino-acid-long sequences derived from a transmembrane precursor βAPP (β-amyloid precursor protein) by sequential proteolytic actions by several proteases named secretases (Checler, 1995). An acidic protease, called β-secretase (identified as BACE1, memapsin 2 or ASP2; Hussain et al., 1999; Lin et al., 2000; Sinha et al., 1999; Vassar et al., 1999; Yan et al., 1999), triggers the first and rate-limiting cleavage liberating C99, the C-terminal fragment of βAPP that harbors the Aβ sequence at its N-terminus. C99 then undergoes an epsilon secretase cleavage (Gu et al., 2001; Passer et al., 2000; Sastre et al., 2001; Weidemann et al., 2002) that releases AICD (APP IntraCellular Domain; Belyaev et al., 2010; Flammang et al., 2012; Goodger et al., 2009) that can act as a transcription factor (Konietzko, 2012; Pardossi-Piquard & Checler, 2012), and APPε. The latter catabolite undergoes an additional C-terminal truncation by both presenilin-dependent (De Strooper et al., 1998) and independent (Armogida et al., 2001) γ-secretases that ultimately liberate “full length” Aβ (flAβ) species (Lefranc-Jullien, Sunyach, & Checler, 2006). The presenilin-dependent γ-secretase is a high molecular weight complex consisting of at least four components, namely presenilin 1 or 2 (Rogaev et al., 1995; Sherrington et al., 1996), nicastrin (Yu et al., 2000), Pen-2 and Aph-1 (Francis et al., 2002). Although the presenilin-independent γ-secretase has yet to be identified, it has been characterized as a serine protease against which a series of isocoumarin blockers have been designed (Petit et al., 2001; Peuchmaur et al., 2013). Once produced, flAβ is bio-transformed by a series of additional modifications by either exopeptidase-mediated N- or C-terminal truncations (Funamoto et al., 2004; Sevalle et al., 2009; Tekirian et al., 1998), glutaminyl cyclization (Hartlage-Rubsamen et al., 2011; Schilling et al., 2008) or internal cleavages (Caillava et al., submitted for publication; Fluhrer et al., 2003; Shi et al., 2003) giving rise to fragments harboring their own aggregation properties, biological functions or toxicities (Wirths et al., 2009). Very little is known about the relative contribution of these various Aβ-related fragments to AD pathology, but several lines of evidence indicate that some of these

fragments or some of the above-described proteins involved in βAPP processing could control p53-dependent cell death. In Alzheimer's disease, neuronal cell death by apoptosis has been a matter of discussion (see http://www.alzforum.org/res/for/journal/detail. asp?liveID=113). The inconsistencies in this field could likely be due to the variability of the biological samples, the post-mortem delays in obtaining anatomical tissues (Anderson, Su, & Cotman, 1996), the wide spreading of the lesions, and the technical limits of sensitivity for in situ detection of apoptotic markers. Nevertheless, several lines of evidence suggest that cell death occurs to a certain extent by apoptosis in AD-affected brains (Kusiak, Izzo, & Zhao, 1996). Thus, in situ examination of the nuclei morphology and DNA fragmentation indicated enhanced apoptotic-like phenotype in the hippocampus and entorhinal cortex of AD-affected patients (Anderson, Stoltzner, Lai, Su, & Nixon, 2000; Su, Anderson, Cummings, & Cotman, 1994). These pro-apoptotic stigmata are in good agreement with a study showing that apoptotic neurons in AD are often associated with enhanced intracellular Aβ42 expression (Chui et al., 2001). Furthermore, a report on the expression of a series of gene products involved in cell death cascades showed an increase of the pro-apoptotic protein Bax-α in AD-affected hippocampus with no alteration of the anti-apoptotic protein Bcl-2 (Sajan et al., 2007). It should be noted, however, that another study reported on a selective increase of Bcl-2 in damaged neurons while it appears decreased in tangles bearing neurons (Su, Satou, Anderson, & Cotman, 1996). Interestingly, not only neuronal cells but also astrocytes could undergo apoptosis in AD-affected cortical areas (Kobayashi et al., 2004). The enhanced cell death possibly occurring in AD is further supported by several observations indicating that βAPP-derived catabolites could indeed trigger apoptosis in cells and animal models. Thus, aggregated Aβ42 correlates with caspase-8 mRNA levels in the temporal region of AD-affected brains (Matsui et al., 2006) and is increased in damaged neurons (Ohyagi et al., 2000). A derivative fragment of Aβ (Aβ25–35), that is not consistently detectable in AD-affected brains but can mimic some of Aβ-related phenotypes (Diaz et al., 2010; Meunier, Leni, & Maurice, 2006), indeed promotes apoptosis in lymphocytes (Velez-Pardo, Ospina, & Jimenez del Rio, 2002) and in PC12 cells (Martin et al., 2001). This Aβ-mediated enhanced neurodegeneration also occurs in vivo in a mouse model of Alzheimer's disease (transgenic mice harboring a presenilin 1 mutation) where Aβ accumulation triggers retinal degeneration (Ning, Cui, To, Ashe, & Matsubara, 2008). Besides Aβ and its derivatives, various C-terminal fragments of βAPP have been shown to induce cell death. Thus, low concentrations of the recombinant C-terminal βAPP fragment CT105 triggers apoptosis in astrocytes (Bach et al., 2001). Higher doses of the same fragment (10 μM) disrupt membrane integrity as assessed by lactate dehydrogenase release from primary cultured neurons (Kim & Suh, 1996), prevents uptake (Kim, Park, & Suh, 1998) and increases intracellular concentrations of calcium (Kim et al., 2000) thereby dramatically perturbing cellular calcium homeostasis. This set of data agrees well with a study demonstrating an association between excitotoxicity, DNA fragmentation and caspase-3 activation (Masliah, Mallory, Alford, Tanaka, & Hansen, 1998) in AD brains and corroborates a study showing that Aβ affects Ca2+ homeostasis and behavioral deficits of transgenic mice via an interplay with ryanodine receptors (Oulès et al., 2012). Finally, we showed that C31, a caspase-3-derived C-terminal fragment of βAPP that accumulates in AD brains (Lu et al., 2000), enhances toxicity in TSM1 neurons although by a caspase-3 independent mechanism (Dumanchin-Njock, Alves da Costa, Mercken, Pradier, & Checler, 2001). βAPP-derived fragments can also modulate p53. For example, Aβ42 directly activates the transactivation of the p53 promoter (Ohyagi et al., 2005). Moreover, oxidative DNA damage triggers Aβ42 translocation into the nucleus along with increased p53 mRNA levels. Finally, of most interest, in transgenic mouse models of AD and in AD brains, neurons that harbor ill-shaped morphology display both Aβ42 and p53 accumulation (Ohyagi et al., 2005). On a more functional stand point, p53 blockade by its transcriptional inhibitor pifithrin-α (Komarov


et al., 1999a, 1999b) lowers microglial responsiveness to the toxicity induced by Aβ-related peptides (Davenport, Sevastou, Hooper, & Pocock, 2010). Besides Aβ, the ε-secretase-derived βAPP fragment AICD that can act as a transcription factor (Pardossi-Piquard & Checler, 2012) also controls p53 at a transcriptional level (Alves da Costa, Sunyach et al. 2006; Ozaki et al., 2006). It should be noted that cell cycle re-entry has been postulated to account for exacerbated neuronal apoptosis in various neurodegenerative diseases (Folch et al., 2012) and that soluble Aβ itself could trigger neuronal cell cycle re-entry (Seward et al., 2013). Although the latter phenotype appears to be mediated by tau protein (Seward et al., 2013), the above-described direct link between Aβ and p53, that is clearly involved in cell cycle control (Chandler & Peters, 2013; Nakamura, 2004), could be envisioned as a molecular pathway accounting for, at least in part, the pro-apoptotic lesions observed in AD. The overall above-cited data concur to suggest the possibility of an increased cell death in AD, a process probably linked to the alteration of βAPP processing. They also indicate a functional interplay between the βAPP-related fragments and the tumor suppressor p53, therefore, suggesting a possible direct link between the two cellular partners. Several studies examined more directly the relevance of p53 as a marker/effector of AD pathology. Kitamura and colleagues compared p53-like immunoreactivity in post-mortem AD-affected brains and controls. They reported a consistent increase in p53 expression in the pathological temporal cortex areas, and more precisely at the glial level (Kitamura et al., 1997). This astrocyte-selective p53 label was partly confirmed by a concomitant study showing that indeed, p53 detection by in situ immunolocalization revealed enhanced p53 expression not only in astrocyte and oligodendrocyte populations of frontal and temporal lobes but also in numerous cortical neurons (de la Monte, Sohn, & Wands, 1997). Of interest, this increased p53 expression coincided with enhanced DNA fragmentation and Fas expression (de la Monte et al., 1997), indicating that p53 could contribute to cell death in AD brains. It should be noted that a co-increase in p53 and Fas expressions was also observed in Down syndrome affected brains (Seidl, FangKircher, Bidmon, Cairns, & Lubec, 1999), another pathology displaying AD-like histological alterations (Lott, 1982; Mann, 1988) likely due to the extra copy of the chromosome 21 that bears the βAPP-encoding gene (Holtzman & Epstein, 1992). These studies were confirmed by more recent data showing enhanced levels of p53 in the superior temporal gyrus (Hooper et al., 2007) as well as in the inferior parietal lobule of AD-affected brains (Cenini, Sultana, Memo, & Butterfield, 2008). Interestingly, the latter group correlated the enhanced p53 expression with markers observed in oxidative stress-induced neuronal cell death (Cenini et al., 2008). The parallel increase observed for p53 and cell death in AD-affected brains could be understood with respect to the widely documented function of p53 in cell cycle arrest, DNA repair and apoptosis (Aylon & Oren, 2011; Bourdon, De Laurenzi, Melino, & Lane, 2003; Levine & Oren, 2009; Vogelstein & Kinzler, 1992). Thus, enhanced p53 expression could account for increased cell death observed in AD brains. This apparently clear participation of p53 in AD could likely be discussed when considering structural aspects of p53. Several studies indicated that p53 could be conformationally altered in AD (Buizza et al., 2012). Thus, unfolded p53 was immunologically characterized in fibroblasts of AD-affected patients at early stages of the disease (Uberti, Lanni, Racchi, Govoni, & Memo, 2008; Uberti et al., 2006). Interestingly, these structural alterations of p53 have functional consequences since unfolded p53 species harbor altered DNA binding properties and impairment of its transcriptional activity (Uberti et al., 2006). This agreed well with a previous report indicating that human skin fibroblasts derived from AD-affected patients show drastic alterations in the molecular effectors of p53-dependent cell death pathways. Notably, several of the classic p53-targeted genes were not activated when these fibroblasts were challenged by several pro-apoptotic triggers (Uberti et al., 2002). This could appear at first sight paradoxical when considering enhanced central apoptosis in AD brains. However, it should be noted that such

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unfolded p53 species were not detected in the brain and that they were observed very early in the blood of MCI-affected patients (Lanni et al., 2010). Therefore, one can consider that unfolded p53 could be a peripheral and early signature of AD, independent of the cell death observed in the central nervous system. Alternatively, one can also envision a dual involvement of p53, the structural modifications of which could be seen as a protective mechanism at early stages of the disease (Lanni et al., 2010), while the increased levels of residual wild-type biologically active p53 would overcome this protective phenotype and contribute to the neuropathological process later. p53 can also control the expression of proteins involved in AD pathology and indirectly influence the course of the disease without directly affecting proteins considered as its classical targets. Thus, the four proteins involved in the build-up of a biologically active high molecular weight γ-secretase complex (Edbauer, Kaether, Steiner, & Haass, 2004; Kimberly et al., 2003; Takasugi et al., 2003) are regulated or regulate p53 (Checler, Dunys, Pardossi-Piquard, & Alves da Costa, 2010). AD-linked pathogenic mutations in presenilin 1 (Guo et al., 1999) or presenilin-1 depletion (Roperch et al., 1998) activate caspases and thereby, enhance cell vulnerability to apoptotic stimuli by yet poorly understood mechanisms. Conversely, presenilin-2-associated proapoptotic phenotype has been consistently linked to p53. Thus, presenilin 2 and its presenilinase-derived C-terminal counterpart increase p53 expression (Alves da Costa, 2005; da Costa, Masliah, & Checler, 2003; Alves da Costa, Mattson, Ancolio, & Checler, 2003; Alves Da Costa, Paitel, Vincent, & Checler, 2002; Alves da Costa et al., 2002) likely via the release of AICD that acts as a transcriptional activator of p53 promoter transactivation (da Costa, Dunys, et al., 2006; Alves da Costa, Sunyach, et al., 2006). This presenilin-driven modulation of p53 accounts for the functional interplay observed between presenilins and another member of the γ-secretase complex, namely Pen-2 (Dunys et al., 2009). Conversely, we recently documented a direct p53-dependent control of mRNA and protein levels of both presenilins 1 and 2 (Duplan, Sevalle, et al., 2013) in agreement with a previous study showing that p53-dependent cell death was accompanied by a modulation of presenilin-1 expression (Roperch et al., 1998). Finally, the other members of the presenilin-dependent γ-secretase complex, namely nicastrin (Pardossi-Piquard et al., 2009), Aph-1 and Pen-2 (Campbell et al., 2006; Dunys et al., 2007) are able to repress p53 in various cell and animal models. Overall, this complicated scheme (Fig. 1) that links p53 to all the members of the γ-secretase complex and thereby to the production of various βAPP-catabolites such as Aβ and AICD that can both act as p53 modulators (da Costa, Dunys, et al., 2006; Alves da Costa, Sunyach, et al., 2006; Ohyagi et al., 2005) likely accounts, at least in part, to the observation of concomitant enhancements of p53 and cell death in AD. One cannot preclude the possibility that tau protein that accumulates in the intracellular compartments of dying neurons in AD (Lee & Trojanowski, 1999; Spillantini & Goedert, 1998; Yankner, 1996) could contribute to AD-associated apoptosis. Thus, tau hyperphosphorylation is associated with, and even precedes, apoptosis in neuroblastoma cells (Mookherjee & Johnson, 2001). It is noteworthy that p53 was shown to increase tau phosphorylation in human cells (Hooper et al., 2007). Interestingly, the peptidyl prolyl cis/trans isomerase Pin1 could be seen as a potential regulator of p53-dependent phosphorylation of tau as it was shown to increase AP-1-mediated stabilization of p53 and to influence the ability of tau to bind microtubules (Takahashi, Uchida, Shin, Shimazaki, & Uchida, 2008). Furthermore, Pin1 was also reported to modulate the phosphorylation state of βAPP (Takahashi et al., 2008) at threonine 668 (Ma, Pastorino, Zhou, & Lu, 2012), which is recognized as a key residue for βAPPassociated control of synaptic plasticity, memory process and signaling properties (Lombino, Biundo, Tamayev, Arancio, & D'Adamio, 2013). Nevertheless, it remains to be established definitively whether Pin1 expression is modulated at early or late stages of AD pathology since previous studies led to apparent conflicting data probably due to differences in post-mortem samples. Thus, MCI-affected brains appear

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Fig. 1. Functional interplay between p53 and members of the γ-secretase complex. Cross-talk and feed-back between p53 and the four members of the γ-secretase complex (PS1 or PS2, Aph-1, nicastrin (Nct) and Pen-2). Arrows indicate modulations observed following over-expression of the proteins indicated at the starting points of arrows (red arrows, inhibition (−); blue arrows, activation ( )). PS2NNPS1 means that PS2 is dominant over PS1 for p53-dependent proapoptotic phenotype (see Alves da Costa, Paitel, Mattson, et al., 2002).

to display higher levels of Pin1 than controls (Pastorino et al., 2012), while Pin1 expression apparently decreases as long as AD progresses (Wang et al., 2007), indicating that Pin1-linked modulation of p53, if it has a genuine role in AD pathology, should be considered as an early event in the course of the disease. 3. p53 and Parkinson's disease Parkinson's disease (PD) comes in second rank of neurodegenerative diseases in terms of number of affected patients worldwide. The histopathological hallmarks were described about a century ago and it is now admitted that the main brain locus degenerating in the disease is a small area in the ventral midbrain, the pars compacta of the substantia nigra that is mainly composed of dopaminergic neurons (Barzilai & Melamed, 2003). PD-affected substantia nigra harbors intracellular inclusions named Lewy bodies (Goedert, Spillantini, Del Tredici, & Braak, 2013) filled with a protein named α-synuclein (Gwinn-Hardy & Singleton, 2002; Trojanowski & Lee, 1998). Unlike AD, the occurrence of cell death in PD is a matter of consensus (Hartmann & Hirsch, 2001; Lev, Melamed, & Offen, 2003; Maruyama & Naoi, 2002; Nagatsu, 2002; Schapira & Jenner, 2011). Histological and molecular biologic approaches consistently revealed alterations in in situ DNA fragmentation and the number of Tunel-positive cells (Mochizuki, Goto, Mori, & Mizuno, 1996; Tatton & Kish, 1997) as well as in the levels and activities of various cellular effectors participating in cell death control such as caspase-3, caspase-9, cytochrome C and p38 MAPK (Blandini et al., 2006; Junn & Mouradian, 2001). This was confirmed at the level of a single neuronal cell by microarray gene profiling (Simunovic et al., 2009). The main conclusion of these studies was corroborated by a vast number of works performed on toxin-based cellular and animal models that exhibit exacerbated cell death (Gandhi & Wood, 2005). Thus, chronic infusion of both rotenone and MPTP toxins

in murine species mimics the histological features observed in PD (Betarbet et al., 2000; Fornai et al., 2005). It should be noted that protein aggregates often occur in neurodegenerative diseases (Checler, Alves da Costa, Ancolio, Lopez-Perez, & Marambaud, 2000; Huang & Figueiredo-Pereira, 2010) which lead to the impairment of the proteasomal machinery (Bence, Sampat, & Kopito, 2001). Proteasomal dysfunction is often accompanied by cell death as has been evidenced by the pro-apoptotic phenotype triggered by the proteasome inhibitor lactacystin (Fenteany & Schreiber, 1998; Fenteany et al., 1995; Zhou et al., 2010). Interestingly, several studies indicate that indeed, proteasome-mediated degrading process is impaired in PD. Thus, Blandini and colleagues reported on the reduction of the proteasome activity in PD and unraveled an inverse relationship between PD duration and severity with 20S proteasome activity (Blandini et al., 2006). p53 is among the various substrates that could accumulate in response to proteasome defect (Vogelstein, Lane, & Levine, 2000), as it undergoes degradation by Mdm2 in a proteasomedependent manner (Haupt, Maya, Kazaz, & Oren, 1997; Kubbutat, Jones, & Vousden, 1997). In good agreement with the above-cited observations, p53 is affected in PD experimental models and in PD-affected brains. Mogi and Colleagues showed that p53-like immunoreactivity is higher in the caudate nucleus but not in the substantia nigra of PD-affected brains (Mogi, Kondo, Mizuno, & Nagatsu, 2007). Lee et al. showed that a metabolically stable nitrated form of p53 is detected in dopaminergic cells dying in response to nitric oxide stress (Lee, Kim, Choi, Ha, & Kim, 2006) and the dopaminergic toxin 6-hydroxydopamine (Nair, 2006). Again, proteasomal inhibition in dopaminergic cells triggers p53-dependent cell death (Nair, McNaught, Gonzalez-Maeso, Sealfon, & Olanow, 2006). The involvement of p53 in 6-hydroxydopamine-linked dopaminergic cell death was confirmed by genetic inactivation of p53 expression by siRNA (Biswas, Ryu, Park, Malagelada, & Greene, 2005) and by


a pharmacological approach aimed at blocking p53 transcriptional activity by pifithrin-α (Komarov et al., 1999a, 1999b). The latter inhibitor proved useful in prolonging the survival of dopaminergic neural grafts in 6-hydroxydopamine-lesioned rat model of PD (Chou, Greig, Reiner, Hoffer, & Wang, 2011). Other toxin-based models of PD corroborated these data. The treatment of PC12 cells with MPP+, the toxic metabolite of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), triggers an activation of p53 transcriptional activity (Xu, Cawthon, McCastlain, Duhart, et al., 2005; Xu, Cawthon, McCastlain, Slikker, et al., 2005), and p53 knockout neurons show resistance to MPTP treatment (Trimmer, Smith, Jung, & Bennett, 1996). Recently, p53 was shown to be involved in growth arrest triggered by another dopaminergic neuronal toxin, rotenone, (Wu et al., 2013) and to contribute to rotenoneinduced degeneration in rat neurons and PC12 cells (Goncalves et al., 2011). The postulate of a contribution of p53 to PD pathology was significantly reinforced by data derived from genetic aspects of the disease (Corti, Lesage, & Brice, 2011). PD could be of sporadic or familial origin (Gasser, 1998; Gosal, Ross, & Toft, 2006; Houlden & Singleton, 2012; Morris, 2005; Rosner, Giladi, & Orr-Urtreger, 2008). Familial PD could follow either autosomal dominant or autosomal recessive inheritance (Houlden & Singleton, 2012; Kumar, Lohmann, & Klein, 2012; Trinh & Farrer, 2013). Autosomal recessive cases of PD are essentially due to mutations in three genes encoding parkin (Kitada et al., 1998), PINK-1 (for PTEN-induced kinase-1, Valente et al., 2004) or DJ-1 (Bonifati et al., 2003) while autosomal dominant inherited cases are linked to mutations principally located on genes encoding α-synuclein (ChartierHarlin et al., 2004; Polymeropoulos et al., 1997; Singleton et al., 2003) and leucine-rich repeat kinase 2 (LRRK2) (Paisan-Ruiz et al., 2004; Zimprich et al., 2004). The main functions of the above-cited proteins and the alterations associated with pathogenic mutations have been extensively studied and reviewed. Parkin has been described as an E3-ubiquitin ligase (Mizuno, Hattori, Mori, Suzuki, & Tanaka, 2001; Shimura et al., 2000) but could also act as a transcription factor (da Costa et al., 2009; Duplan, Sevalle, et al., 2013; Sunico et al., in press). PINK-1 is a serine/ threonine protein kinase (Klein & Schlossmacher, 2007), while DJ-1 is mainly described as an oxidative stress sensor and chaperone protein (da Costa, 2007; Olzmann et al., 2003). Concerning α-synuclein, several studies consistently showed that this protein regulates cell death (Albani et al., 2004; da Costa, Ancolio, & Checler, 2000; Burke, 1999; Chandra, Gallardo, Fernàndez-Chàcon, Schlüter, & Südhof, 2005; Choi et al., 2006; Suh & Checler, 2002) and many additional functions (Alves da Costa, 2003; Surguchov, 2008), while LRKK2 is a kinase that controls the mitogen-activated protein kinase-related pathway (Gloeckner, Schumacher, Boldt, & Ueffing, 2009). Overall, the functions ascribed to the proteins involved in familial PD are closely linked to the control of protein degradation and cell death. In addition, there are several experimental clues linking these proteins to p53 (da Costa & Checler, 2011). α-Synuclein protects neuronal cells challenged with pro-apoptotic effectors (da Costa et al., 2000) by lowering p53 expression and transcriptional activity in cells (Alves Da Costa, Paitel, Vincent, et al., 2002), a phenotype that is abrogated by the A53T pathogenic mutation (da Costa et al., 2000). These observations are supported by the demonstration that p53 accumulates in mitochondria in A53T-expressing transgenic mice (Martin et al., 2006). There exists an apparent paradox between the fact that α-synuclein appears to be toxic rather than protective at high concentrations in dopaminergic cell lines and in tissues. We showed that 6-hydroxydopamine, (6OHDA) which is a natural pro-oxidant and toxic dopamine derivative, triggers both α-synuclein aggregation and proteasomal inhibition and blocks α-synucleinmediated protection against staurosporine-induced caspase-3 activation (da Costa, Dunys, et al., 2006; Alves Da Costa, Paitel, Vincent, et al., 2002; Alves da Costa, Sunyach, et al., 2006). The 6OHDAassociated blockade of α-synuclein function could be prevented by

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anti-oxidant (da Costa, Dunys, et al., 2006) and reversed by overexpression of the α-synuclein congener, β-synuclein (da Costa, Masliah, et al., 2003; Alves da Costa, Mattson, et al., 2003). Interestingly, the latter protein is protective, lowers staurosporine-induced p53 activation and restores α-synuclein's ability to repress p53 likely by modulating Mdm2mediated p53 degradation (da Costa, Masliah, et al., 2003; Alves da Costa, Mattson, et al., 2003). This agrees well with a study showing that β-synuclein could control Akt that acts as an upstream effector of the Mdm2-linked cascade ultimately leading to p53 phosphorylation and nuclear degradation (Hashimoto et al., 2004). Finally, synphilin-1, which is a component of Lewy bodies (Wakabayashi et al., 2000) and interacts with α-synuclein physically and functionally (Engelender et al., 1999; Smith et al., 2010), undergoes a caspase-3 mediated cleavage giving rise to a C-terminal product able to lower p53 at the level of the promoter, mRNA and protein expression (Giaime et al., 2006). Several lines of evidence indicate that proteins involved in recessive cases of PD also interact functionally with p53. The most convincing evidence came from our recent report on a novel function of parkin as a transcription factor able to repress p53 (da Costa & Checler, 2010). This phenotype was independent of parkin-linked ubiquitin ligase activity and was abrogated by pathogenic mutations (da Costa et al., 2009). Indeed, parkin physically interacts via its RING1 domain with the p53 promoter region (da Costa et al., 2009). Interestingly, parkinassociated control of p53 could trigger downstream events, and notably, could control DJ-1 by a molecular cascade involving first p53 followed by another transcription factor involved in cellular response to endoplasmic reticular stress, XBP-1S (Duplan, Giaime, et al., 2013). Obviously, the direct or indirect participation of the ubiquitin-ligase-dependent function of parkin in the control of the degradation process of p53 could not be totally precluded. In this context, it is interesting to note that several parkin substrates are indeed upstream regulators of p53-dependent pathways. Also interesting was the demonstration that a cytosolic protein displaying high homology with parkin C-terminus (thus referred to as PARC, parkin-like ubiquitin ligase) controls the subcellular localization of p53 and p53-mediated apoptosis even in unstressed cells (Nikolaev, Li, Puskas, Qin, & Gu, 2003). Moreover, p53 trafficking could be proteolytically regulated by calpain-mediated PARC degradation (Woo, Xue, Liu, McBride, & Tsang, 2012). A functional crosstalk between p53 and parkin was also recently documented. Accordingly, p53 directly regulates the transcription of parkin (Viotti et al., in press; Zhang et al., 2011) and could account for the interplay taking place in brain cancers (see below). The functional interaction of DJ-1 with p53 and notably, its ability to repress p53, has been reported by two groups (da Costa, 2007; Ottolini, Cali, Negro, & Brini, 2013) although one study showed that DJ-1 could positively regulate p53 transcriptional activity (Shinbo, Taira, Niki, Iguchi-Ariga, & Ariga, 2005). More generally, DJ-1 was found to lower p53 expression and activity in both mammalian cells (Fan, Ren, Fei, et al., 2008; Fan, Ren, Jia, et al., 2008; Giaime et al., 2010) and zebrafish (Bretaud, Allen, Ingham, & Bandmann, 2007). Thus, mutations that render DJ-1 resistant to caspase-6-mediated proteolysis abolish the production of a DJ-1 C-terminal fragment that is able to repress p53 at both transcriptional and post-transcriptional levels (Giaime et al., 2010). This was corroborated by knockout (Bretaud et al., 2007) and over-expression approaches (Fan, Ren, Fei, et al., 2008; Fan, Ren, Jia, et al., 2008) showing that DJ-1 could also control the levels of the p53 transcriptional target, Bax. Again, a feed-back mechanism by which p53 apparently controls DJ-1 was demonstrated by a proteomic study designed to identify new p53 phosphorylated targets in HCT116 cancer cells (Rahman-Roblick et al., 2008). Also interesting was the observation that caspase-6 could yield DJ-1 N- and C-terminal fragments with distinct functions as it is the case for cellular prion protein PrPc (GuillotSestier & Checler, 2012a) since the caspase-6-derived N-terminal product triggers apoptosis by increasing reactive oxygen species (Robert et al., 2012).

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Few reports link LRRK2 and p53. It should be noted, however, that LRRK2 phosphorylates various kinases of the mitogen-activated protein kinase cascades (Gloeckner et al., 2009). Since some of these kinases are upstream effectors of p38 MAP Kinase (p38 MAPK) that phosphorylates p53 (Perfettini et al., 2005), one could speculate about a LRRK2associated and p38 MAPK-linked modulation of the p53 cellular pathways, although this requires final demonstration. Supporting this hypothesis, it was recently demonstrated that LRRK2-deficiency apparently triggers enhanced expression of phosphorylated p53 in human neural progenitor cells, indicating that LRRK2 could indeed exert a p53-dependent protective role in dopaminergic neurons (Milosevic et al., 2009). Finally, there is no clear evidence for the control of p53 by PINK-1. However, the simple assertion that PINK-1 induces PTEN, which undergoes p53-mediated transactivation (Stambolic et al., 2001), makes plausible a direct or indirect functional link between p53 and PINK-1. Overall, both histological and biological evidence concur to propose p53 as a main contributor of exacerbated cell death taking place in PD (Fig. 2).

4. p53 and prions Prion diseases have been at the origin of a revolutionary concept stating that pathogenic proteins could be, per se, considered as infectious triggers that can accumulate, spread and propagate without contribution of any nucleic acid (Prusiner, 1998). In animals and humans, prion-related pathologies mainly correspond to either scrapie, bovine spongiform encephalopathies, Creutzfeldt–Jakob and Gerstmann– Sträussler–Scheinker diseases (Aguzzi & Polymenidou, 2004; Collinge, 2005; Weissmann, Enari, Klöhn, Rossi, & Flechsig, 2002). Pathogenic prion (PrPsc) is a proteolytically resistant protein that results from the biophysical conversion of a physiological and ubiquitous protein called cellular prion (PrPc). The latter congener is essential for the infectious process since several studies indicate that cells or animals devoid of PrPc fully resist infection by PrPsc-enriched preparations (Brandner et al., 1996; Büeler et al., 1993; Sailer, Bueler, Fischer, Aguzzi, & Weissmann, 1994).

Fig. 2. Functional interplay between p53 and various proteins responsible for familial Parkinson's disease. Cross-talk and feed-back between p53 and proteins involved in autosomal dominant (α-synuclein and LRRK2) and autosomal recessive (parkin and DJ-1) forms of Parkinson's disease. The interplay between p53 and proteins indirectly linked to PD (synphilin-1 and HtrA2/Omi) as well as the influence of several toxins linked to PD-like models (chemicals) are also indicated. Arrows indicate modulations observed following over-expression of the proteins indicated at the starting points of arrows or after toxin treatments (red arrows, inhibition (−); blue arrows, activation ( )).

Several studies indicated that scrapie-mediated infection of cells, animals and humans triggers cell death markers enhancement. Thus, various regions of Creutzfeldt–Jakob-affected brains show increased expression of caspases-3 and -9, Bax and the Poly-ADP-ribose polymerase PARP (Kovacs & Budka, 2010). Furthermore, immunohistochemical analysis of natural scrapie-infected sheep indicates that Bax co-distributes with PrPsc deposition (Lyahyai et al., 2007). This was corroborated with the demonstration that active caspase-3 expression was increased in mice inoculated with infectious scrapie-enriched preparations (Drew et al., 2011). Finally, a scrapie-infected neuronal cell line shows morphological and biochemical alterations reminiscent of apoptotic hallmarks (Schatzl et al., 1997). The above-described set of observations did not delineate the relative contribution of PrPc vs PrPsc to the apoptotic process. Several studies based on the modulation of cellular PrPc levels or on the use of recombinant PrPc support the view that this protein could indeed harbor a proapoptotic potential. Thus over-expression of PrP23–230 reduces viability and increases apoptosis of HeLa cells (Li et al., 2011). This agreed well with the demonstration that the reduction of endogenous PrPc by RNA silencing indeed lowers T lymphoblastoid CEM cell responsiveness to Fas-induced apoptosis (Mattei et al., 2011). This effect appears to be linked to a PrPc redistribution at the ER-mitochondrial contacts that ultimately lead to an alteration of mitochondrial membrane potentials and to the release of cytochrome c (Sorice et al., 2012). Interestingly, an unbiased search for PrP-related toxic species led to the identification of an alpha helical-enriched form of PrPc that triggers apoptosis and autophagy (Zhou, Ottenberg, Sferrazza, & Lasmezas, 2012). It should also be noted that several studies aimed at delineating PrPc-related toxicity used a 21-amino-acid long peptide referred to as PrPc106–126 that mimics some of the PrPsc-associated phenotypes (Brown, 2000; Singh et al., 2002) and that was shown to be neurotoxic both in vitro and in vivo. PrPc106–126 increases DNA fragmentation, the number of Tunel-positive cells, p38 MAPK and active form of caspase-3 (Jeong et al., 2011). Consistent with the idea that PrPc could undergo proteolysis by the proteasome (Amici et al., 2010; Cecarini et al., 2010; Wang, Wang, Sy, & Ma, 2005), it was demonstrated that proteasomal inhibition potentiated PrPc-associated caspase-3 activation (Paitel, Alves da Costa, Vilette, Grassi, & Checler, 2002). It should be noted that a study indicated that PrPc could lower apoptotic response in a bacterial model of infection (Ding et al., 2013). In a more general cellular context, PrPc could behave as a pro-survival effector instead of triggering cell death (Linden et al., 2008). Particularly interesting is a series of studies showing that PrPc physically interacts with the STI1 (Lopes et al., 2005; Zanata et al., 2002), thereby initiating a signaling cascade (Chiarini et al., 2002) ultimately leading to PKA and ERK1 activation (Caetano et al., 2008). These studies, which could appear at first sight contradictory with the PrPc-related proapoptotic hypothesis, could likely be explained by pro-apoptotic challenges, cell specificity and proteolytic events. Thus, ER-stressinduced caspase activation and apoptosis could be enhanced by PrPc while conversely, PrP c protects cells against H 2 O2 treatment (Anantharam et al., 2008). PrPc-associated resistance to apoptosis could be directly linked to its glycosylation state (Yap & Say, 2011) and cell type (Yap & Say, 2012). More recently, several studies indicated that proteolytic events could participate in the control of PrPc function (Guillot-Sestier & Checler, 2012b). Thus, PrPc is cleaved within the 106–126 toxic sequence by ADAM proteases belonging to the class of disintegrins (Vincent et al., 2000; Vincent et al., 2001). One of them also contributes to the shedding of PrPc, thereby releasing the extra domain within the extracellular space (Altmeppen et al., 2011; Taylor et al., 2009). It is of interest to note that the same set of secretases participates in the α-cleavage of both βAPP and PrPc, and that the kinase PDK-1 contributes to a functional cross-talk between βAPP and PrPc via the phosphorylation of ADAM17 and its depletion from the membrane (Checler, 2013; Pietri et al., 2013).


Two distinct lines of evidence indicate that the N-terminal moiety of PrPc is important for its function/toxicity. First, the over-expression of PrPc deleted in its N-terminal region of 80 to 100 amino-acid long segments in PrPc knockout mice leads to a severe ataxia and neuronal loss (Shmerling et al., 1998). Accordingly, neuronal treatment with recombinant human PrPc-90–231 triggers cytosolic accumulation of aggregated fragment that is accompanied by neuronal apoptosis (Thellung et al., 2011). Second, The N1 fragment liberated by ADAM proteases is neuroprotective in vitro and in vivo (Guillot-Sestier, Sunyach, Druon, Scarzello, & Checler, 2009). Therefore, one can envision that α-secretase-mediated cleavage of PrPc is a central mechanism conditioning the overall phenotype associated with intact PrPc levels, and that the cell specific enzymatic machinery targeting PrPc could directly drive the levels of N1/intact PrPc and thereby, could explain the apparently discrepant pro-apoptotic/pro-survival phenotypes observed in the above-described studies. Several lines of evidence indicate that PrPc and its fragments could modulate p53 expression and activity (Guillot-Sestier & Checler, 2012a). First, it was shown that PrPc over-expression sensitized neurons to pro-apoptotic triggers (Paitel, Fahraeus, & Checler, 2003) and increased p53 expression at a post-transcriptional level via the modulation of Mdm2 (Paitel et al., 2003). In agreement, primary cultured neurons derived from PrPc-depleted mice display reduced responsiveness to staurosporine-induced p53 activation (Paitel et al., 2004). This phenotype required PrPc endocytosis as was demonstrated by various mutational and cell biological approaches (Sunyach & Checler, 2005). We showed that the C-terminal counterpart of N1 named C1 yielded by α-secretase cleavage potentiated p53 activation, while another fragment (C2) recovered in PrPsc-affected brains (Chen et al., 1995) and resulting from a downstream cleavage by a yet unknown protease remained biologically inert (Sunyach, Cisse, da Costa, Vincent, & Checler, 2007). Interestingly, N1 protects cells from C1- and PrPcinduced activation of p53 (Guillot-Sestier et al., 2009). This indicates first that ADAM-mediated proteolysis of PrPc could produce fragments with distinct functions (Guillot-Sestier & Checler, 2012a) and second, that the proteolytic events yielding PrPc fragments and regulating the PrPc levels could indeed directly modulate the function of PrPc and its catabolites. Additionally, the 106–126 PrPc fragment increases p53 and lowers the expression of the anti-apoptotic protein Bcl-2 (Jeong et al., 2011). Furthermore, DNA microarray analyses indicated that PrPc triggers significant up-regulation of p53 in PrP-mediated myopathy (Liang et al., 2009). As it has been described for Alzheimer's and Parkinson's diseases, there exists a feed-back control by which p53 controls PrPc levels. Thus, p53 could directly control PrPc promoter transactivation and a functional p53 responsive element has been identified in the promoter region of PrPc (Vincent, Sunyach, Orzechowski, St George-Hyslop, & Checler, 2009). 5. p53 and brain cancers Cancer is a huge public health problem, the prevalence of which is also associated with aging. In contrast to neurodegenerative diseases, the tumorigenesis process is associated with increased proliferation concomitant with drastic reduction of apoptotic responses. Of most interest, several epidemiological studies have found an inverse correlation between the risk of developing several neurodegenerative disorders and cancer (Becker, Brobert, Johansson, Jick, & Meier, 2010; Musicco et al., 2013; Roe, Behrens, Xiong, Miller, & Morris, 2005). This negative relationship raises the question of whether despite being phenotypically divergent, these multifactorial chronic pathologies could share common protein effectors, the function of which would be either altered or exacerbated. Given the major role of p53 in neurodegenerative diseases and brain cancer, one could easily envision p53 as a serious molecular candidate. Brain tumors of glial origin are among the top ten most deadly cancers. Gliomas represent ~80% of all malignant brain tumors (Ohgaki &

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Kleihues, 2007; Wrensch, Minn, Chew, Bondy, & Berger, 2002) and can be classified according to cytological type and grade (Furnari et al., 2007). The most up-to-date classification of gliomas recognized by the World Health Organization (WHO) combines cytological origin and malignancy grade criteria (Louis et al., 2007). Accordingly, gliomas originating from astrocytes, oligodendrocytes or a mix of different glial cell types are respectively named astrocytomas, oligodendrogliomas and mixed gliomas. This cytology-based glioma classification is then refined according to malignancy severity in either low-grade (WHO grade II) or high grade infiltrating gliomas (WHO grades III and IV) (Lu et al., 2000). The low-grade astrocytomas (grade II) are characterized by a faint increase in cellular density in comparison with white substance, the presence of cytological atypias, usually lack of mitotic activity and by the absence of vascular proliferation and necrosis. The anaplastic astrocytoma of grade III is characterized by a more pronounced augmentation of cell density, number of nuclear atypias and mitosis. The astrocytomas of grade IV, better known as glioblastoma multiforme (GBM), present all the characteristics of grade III astrocytomas in addition to a vascular proliferation and necrosis. GBM may be further classified as primary, which develops rapidly de novo, or secondary, which develops through progression from a low-grade tumor. GBM is the most aggressive malignant tumors and is associated with 50% of all gliomas (Ohgaki & Kleihues, 2005a, 2007). Grade I gliomas are mainly represented by pilocytic astrocytomas and represent 50% of gliomas affecting preferentially young children (Villarejo, de Diego, & de la Riva, 2008). They are considered benign and in contrast to infiltrating gliomas, they have a good prognosis. The oligodendrogliomas may be of grade II or III and, even if these two grades present the same cytological characteristics, the WHO classification highlights that an increased mitotic activity and a possible presence of necrosis indicate a progression to a grade III. Moreover, this type of glioma may be distinguished by the strong labeling of the oligo2 biomarker (Colin et al., 2007; Lu et al., 2001; Maries, Dass, Collier, Kordower, & Steece-Collier, 2003). The mixed gliomas, given the difficulty to accurately estimate their composition in astrocytes versus oligodendrocytes, are much more difficult to diagnose. Nevertheless, the WHO recommends the classification of mixed gliomas in grades II to III depending on the malignancy criteria previously described (cellular density, nuclear atypias, mitotic index and presence of vascularization/necrosis). Tumors of distinct cytological type respond differently to the available clinical treatments. Thus, oligodendrogliomas are much more sensitive to chemotherapy than astrocytomas (Behin, Hoang-Xuan, Carpentier, & Delattre, 2003; Cairncross & Macdonald, 1988). The limits of the WHO gliomas classification, based on subjective morphological characteristics, are outlined by the rather large discordance rate (20– 60%) for the diagnosis made by neuropathologists (Coons, Johnson, Scheithauer, Yates, & Pearl, 1997; Mittler, Walters, & Stopa, 1996). This observation drove a huge research effort aimed at delineating key glioma molecular determinants to better understand the causes of glioma genesis and to identify reliable glioma biomarkers to be used in clinics. The search for molecular effectors of gliomas rapidly converged to the demonstration of a key role for p53 in their etiology. p53 is the most frequently mutated gene product in human cancers and especially in nervous system-associated cancers as indicated by the recently released IARC p53 database (Petitjean et al., 2007). According to the R16 IARC TP53 database (R16, November, 2012), the p53 mutation mostly represented in brain tumors is C:G → A:T at CpG sites (39%), located mainly in exons associated with its DNA binding properties (e5–e8), and preferentially affect codons 175, 248 and 273. Moreover, 90% of these mutations are missense mutations that inactivate p53 transcriptional activity and are very deleterious. The prevalence of p53 mutations varies according to the cytological type of the tumor. Thus, this prevalence is high in secondary GBM (70%), moderate in mixed gliomas (40%) and low-grade astrocytomas (50%), and low in pure oligodendrogliomas (Hagel et al., 1996; Kim et al.,

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2010; Louis et al., 2007; Maintz et al., 1997; Mendrysa, Ghassemifar, & Malek, 2011; Ohgaki & Kleihues, 2007, 2011; Watanabe et al., 1997). Moreover, both frequencies of p53 mutations and transcriptional activity are correlated with tumor grade in astrocytomas. Interestingly, p53 mutations are already present in low-grade astrocytomas suggesting that this molecular alteration is an early event in secondary glioblastoma genesis (Mendrysa et al., 2011; Stander, Peraud, Leroch, & Kreth, 2004). This observation also suggests that the evaluation of p53 mutation status may have a prognostic value. Accordingly, even if it is still a matter of debate, the presence of p53 mutations seems to be associated with a poor prognostic in low grade astrocytomas (Kim et al., 2010; Stander et al., 2004) and is irrelevant in GBM (Bleeker, Molenaar, & Leenstra, 2012). Interestingly, several studies have shown a link between p53 mutations and p53 protein accumulation suggesting that an accumulation of p53 would be predictive of p53 mutations (Nozaki et al., 1999; Watanabe et al., 1997). Although the predictive value of p53 mutations due to its protein accumulation is still questioned (Levidou et al., 2010; Stander et al., 2004), we have recently shown that p53 protein levels correlate with tumor grade and p53 mutation frequency in oligodendrogliomas and mixed gliomas (Viotti et al., in press), in agreement with several works based on immunohistochemical approaches (Fulci, Ishii, & Van Meir, 1998; Watanabe et al., 1997; Weller et al., 2009). It is worth noting that, even if the prevalence of p53 mutations is predominantly associated with secondary (65%) compared to primary (28%) GBM (Ohgaki & Kleihues, 2005b; Ohgaki et al., 2004), more recent studies, that included additional sequencing of TP53, revealed that mutations are prevalent in primary GBMs as well (Parsons et al., 2008; Zheng et al., 2008). Not only the frequency but also the distribution of p53 mutations in primary versus secondary GBM is distinct. In secondary GBM, most of p53 mutations (57%) will occur in the hot-spot codons 248 and 273, whereas in primary GBM they appear equally distributed (Ohgaki et al., 2004). As described in previous sections, p53 is a transcription factor that responds to several tumor-related stress conditions by halting the cell cycle in the G1 phase in order to allow DNA repair or increase cell death response (Vousden & Lu, 2002), thereby counteracting putative tumor development. It was not surprising, therefore, to note a tight correlation between cell cycle deregulation and inactivation of p53 by mutations in sporadic glioma genesis. It has been shown that the expression of p21, a p53 transcriptional target and key piece of p53associated cell cycle regulation, is reduced in high-grade astrocytomas (Kirla, Haapasalo, Kalimo, & Salminen, 2003). Moreover, in addition to mutation-linked p53 inactivation, other mechanisms may contribute to loss of function of p53 in gliomas. For example, MDM-2, an E3ligase implicated in p53 targeting to proteasomal degradation (Fakharzadeh, Trusko, & George, 1991; Momand, Zambetti, Olson, George, & Levine, 1992; Oliner et al., 1993), p14ARF, an MDM-2 blocker (Kamijo et al., 1998; Pomerantz et al., 1998) and MDM-4, a negative regulator of p53 transcriptional activity, were shown to be genetically altered in gliomas. MDM2 (14%) and MDM4 (7%) genes are amplified whereas p14ARF is homozygously deleted or mutated in 49% of the cases (“Comprehensive genomic characterization defines human glioblastoma genes and core pathways”, Cancer Genome Atlas Research Network, 2008; Toledo & Wahl, 2007). Interestingly, even if the mutation of p53 is a rare event in pure oligodendrogliomas, the overall contribution of p53 mutations, p14ARFdeletions and MDM2/MDM4 amplifications correlates to tumor grade in this cytological glioma type (Watanabe et al., 2001). Finally, several carcinomas may be associated with inactivation of wild-type p53 due to its sequestration into the cytoplasm (Moll, LaQuaglia, Benard, & Riou, 1995; Moll, Riou, & Levine, 1992). This possibility is specially highlighted by the fact that despite a low p53 mutation rate, primary GBM (Watanabe et al., 1997) manifests a huge accumulation of p53 (Von Eckardstein et al., 1997). Interestingly, it has been shown that p53 mutations are associated with nuclear p53 expression, while wild-type p53 is associated with cytoplasmic expression (Sembritzki, Hagel, Lamszus, Deppert, & Bohn, 2002).

6. Pharmacological and gene therapy strategies targeting p53 As indicated above, p53 plays a key role in both neurodegenerative diseases and brain cancer and remains a premier target of strategies aimed at interfering with either exacerbated cell death or defective apoptosis. Theoretically, in brain tumors where wild-type and mutated p53 are inactivated by either accumulation/aggregation or mutation, respectively, the main approach actually envisioned consists of preventing p53 degradation or restoring its transcriptional activity by means of chaperone molecules allowing the recovery of a structurally and biologically active p53. Conversely, in neurodegenerative diseases where one must counteract enhanced p53-dependent cell death, the main strategy aims at developing pharmacological blockers of p53 transcriptional activity or genetic depletion of p53 by siRNA approaches. In the case of both neurodegenerative diseases and cancer, additional therapeutic strategies could consist of interacting with upstream effectors of the p53-dependent cellular pathways or interfering with downstream effectors of p53 such as microRNAs. p53 can undergo ubiquitination (Lee & Gu, 2010) and, accordingly, its levels are tightly regulated by proteasomal degradation (Scheffner, 1998). Overall, targeting the ubiquitin-dependent proteasomal system has been envisioned as a means to activate the p53 pathway in cancer therapy (Allende-Vega & Saville, 2010; Devine & Dai, 2013). More precisely, it was shown about 20 years ago that p53 physically and functionally interacts with several E3-ligases of the Mdm-X (murine double minute gene) family. Thus, MDM-2 was identified as an oncogenic factor able to inhibit p53 transcriptional activity (Momand et al., 1992) by tightly interacting with its acidic activation domain (Oliner et al., 1993). Thus, Mdm-2 blocks p53-linked cell growth arrest and pro-apoptotic phenotype (Kubbutat et al., 1997). Haupt and colleague indeed demonstrated that MDM-2-mediated inhibition of p53 function resulted from the enhancement of its proteasomal inactivation (Haupt et al., 1997). An additional member of the MDM-X family of ligases, MDM-4, also contributes to the stabilization of p53 (Toledo & Wahl, 2007). Prior to proteasomal degradation, Mdm-X could also behave as a p53 molecular chaperone inducing structural changes and inactivation (Sasaki, Nie, & Maki, 2007; Wawrzynow, Zylicz, Wallace, Hupp, & Zylicz, 2007). Thus, via multi-step mechanisms, Mdm-2 and Mdm-4 act as p53 antagonists and, therefore, have been chemically targeted in order to restore p53-mediated loss of function and enhance cell death in cancer (Maslon & Hupp, 2010); Brown, Cheok, Verma, & Lane, 2011). Chaperoning can translate into various phenotypes. As mentioned above, it can lead to functional inactivation by inducing conformational changes in proteins. Conversely, chaperone molecules can be designed to fix a deleterious conformation and restore native structure and function of denatured proteins. This strategy has been envisioned for p53 since various cancer-related mutations can disrupt its conformation and activity. Natural proteins and chemically designed compounds have been developed with the aim of restoring conformationally native and bioactive p53 species (Bossi & Sacchi, 2007; Brown et al., 2011; Bullock & Fersht, 2001; Friedler, Veprintesev, Hansson, & Fersht, 2003). For example, heat shock protein 90 (HSP90) stabilizes mutant p53 (Blagosklonny, Toretsky, Bohen, & Neckers, 1996; Muller, Ceskova, & Vojtesek, 2005), and its natural inhibitor geldanamycin abolishes HSP90 activity and thereby triggers mutant p53 destabilization and proteasomal degradation (Blagosklonny et al., 1996). Interestingly, geldanamycin apparently affects mutant but not wild-type p53 (Dasgupta & Momand, 1997). Numerous synthetic compounds have been shown to potently restore the defective function of mutant p53 (Brown et al., 2011; Maslon & Hupp, 2010). Examples include a nonapeptide CDB3, which has been shown to help maintain the native conformation of newly synthesized mutant p53 and can restore the DNA-binding ability of mutant p53 (Friedler et al., 2002). More recently, a small molecule physically interacting with the DNA binding domain of p53 was shown to restore the normal function of various p53 mutants and, interestingly also to prevent the ubiquitination and proteasomal


degradation of wild-type p53 by HDM-2 (the human counterpart of Mdm-2) (Demma et al., 2010). In neurodegenerative diseases, putative neuroprotective therapeutic approaches include consideration of the hypothesis that p53 plays a key role in the observed exacerbated cell death. Accordingly, the main strategy consists of the design and study of inhibitors of p53 transcriptional activity, in agreement with the fact that this function controls the levels of its pro-apoptotic transcriptional targets (Bourdon et al., 2003; Brown, Lain, Verma, Fersht, & Lane, 2009; Levine & Oren, 2009). Komarov and colleagues described the first potent inhibitor of p53 transcriptional activity and apoptosis named pifithrin-α (Komarov et al., 1999a, b). Its very first utilization was not linked to neurodegenerative disease treatment but to the cancer field. In mice, pifithrin-α prevents the side effects of deleterious apoptosis associated with chemotherapy and radiotherapy in healthy cells surrounding the treated tumor (Gudkov & Komarova, 2005; Komarov et al., 1999a, 1999b). Other inhibitors of p53 have been described as well (Zhu et al., 2002). Most of these p53 inactivators have been validated in AD and PD models. MPTP administration mimics PD-related histological hallmarks and increases DNA fragmentation and p53/Bax signaling (Eberhardt & Schulz, 2003). Intraperitoneal injection of pifithrin-α in MPTP-treated mice reduced nigrostriatal dopaminergic cell damage and rescued motor impairment (Duan et al., 2002). Interestingly, daily administration of pifithrin-α for five days also favors the survival of grafted dopaminergic cells in the striatum of the rats 6-OHDA-induced lesion model of PD. In this animal model, pifithrin-α reinforced the graft-associated improvement of cognitive deficit, reduced the number of Tunel-positive cells and increased tyrosine hydroxylase expression in dopaminergic grafts. Interestingly, this protective phenotype was not observed after grafting of cortical tissue transplants (Chou et al., 2011). In experimental models of AD, pifithrin-α has also proved effective in blocking various Aβ-related toxic phenotypes. This inhibitor prevents Aβ-induced cell death, stabilizes mitochondrial function and reduces caspase activation in hippocampal cell cultures (Culmsee & Landshamer, 2006). Furthermore, in cortical neurons, Aβ increases p53 and its target Bax and perturbs lysosomal function. All these effects are rescued by pifithrin-α and p53 siRNA approach (Fogarty et al., 2010). Finally, it has been reported that Aβ could increase apoptosis in microglia. In AD afflicted brains, the number of apoptotic microglial cells increases (Lassmann et al., 1995; Yang et al., 1998) and this is accompanied by enhanced expression of p53 (Davenport et al., 2010; Kitamura et al., 1997). Both Aβ-related phenotypes are reduced by pifithrin-α (Davenport et al., 2010). Other p53-directed therapeutic strategies applicable to both neurodegenerative diseases and cancer could consist of increasing/repressing its expression by genetic approaches or by interfering with either upstream effectors of the p53 pathway or downstream targets of this tumor suppressor. Targeting the p53 gene was envisioned about twenty years ago (Fulci et al., 1998). Adenoviral expression of p53 revealed the effectiveness of such approach in cells (Fujiwara et al., 1994) without apparent drastic side effects even in normal cells (Bossi et al., 2004; Scardigli et al., 1997). Although viral expression of p53 led to contrasting results in human trials (Moon, Oh, & Roth, 2003; Zeimet and Marth, 2003), the clinical interest in such an approach remains, particularly when combined with conventional chemo- or radio-therapies (Bossi et al., 2004). Conversely, siRNA-linked silencing of mutant p53 reduces cell proliferation and therefore could appear as a promising strategy for both bladder (Zhu et al., 2013) and breast cancer therapy (Braicu, Pileczki, Irimie, & Berindan-Neagoe, 2013). Numerous and interconnected molecular pathways control p53 cellular homeostasis, subcellular localization and transcriptional/ post-transcriptional events that drive several fundamental p53dependent cellular functions via the modulation of various p53 transcriptional targets. These effectors and targets often interplay and contribute to positive or negative regulatory loops (Harris & Levine, 2005) building a very complex cellular network. It is,

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therefore, difficult to envision a selective pharmacological modulation of a given target, particularly because compensatory mechanisms could occur through molecular intermediates that could contribute to additional p53-independent phenotypes. Another opportunity for a more selective approach came from the recent interest in microRNA research (Chen & Rajewsky, 2007; Kloosterman & Plasterk, 2006; Valencia-Sanchez, Liu, Hannon, & Parker, 2006) and the demonstration that p53 indeed can control microRNA levels (Hermeking, 2007). Several reports concomitantly and consistently documented microRNA of the miR-34 family as p53 targets (Bommer et al., 2007; Chang et al., 2007; Corney, Flesken-Nikitin, Godwin, Wang, & Nikitin, 2007; He et al., 2007; Raver-Shapira et al., 2007). Interestingly, miR-34 appears inactivated in cancer cells (Hermeking, 2010). Therefore, restoring miR-34 expression could prove useful to circumscribe chemotherapy resistance in cancer cells. Whether inactivating miR-34 could allow reduction of exacerbated p53-dependent cell death in neurodegenerative disease remains to be examined. 7. Concluding remarks Since the initial clues for the presence of a new protein modulated by SV40 cell infection, more than 68,000 papers have been published on p53, and still 3500 in 2013. This clearly underlines the huge interest in this protein now considered as a main molecular factor defective in carcinogenesis. The key role of p53 now spreads over many other fundamental processes, and the control of its homeostasis by transcriptional and post-transcriptional regulatory mechanisms represents central means to maintain normal cellular physiology. More recently, it appeared that p53 dysfunction could contribute to exacerbated cell death observed in various neurodegenerative diseases. Thus, either increasing/restoring normal p53 function in cancers or reducing p53dependent cell death in neurodegenerative diseases could be seen as tempting therapeutic strategies, and multiple approaches described above could be envisioned. The real challenge remains to modulate p53 function in pathological contexts without triggering serious putative deleterious effects due to the impairment of physiological functions of this pleiotropic protein. Progresses in the design of more selective, potent and bio-available compounds or improvements in alternative genetic approaches ultimately leading to the modulation of p53 function can be reasonably but optimistically envisioned in a rather close future with the aim to prevent, arrest or at least slow down the onset and/ or progression of tumorigenesis and neurodegenerative processes. Conflict of interest statement The authors declare that there are no conflicts of interest. Acknowledgments This work has been developed and supported through the LABEX “Excellence Laboratory Program Investment for the Future” Development of Innovative Strategies for Transdisciplinary Approach to Alzheimer's disease. We wish to thank the Conseil Général des Alpes Maritimes for its constant support. CAC is a recipient of a Hospital Contract for translational research (CHRT) between INSERM and the Hospices civils de Lyon. References Aguzzi, A., & Polymenidou, M. (2004). Mammalian prion biology: one century of evolving concepts. Cell 116, 1–20. Albani, D., Peverelli, E., Rametta, R., Batelli, S., Veschini, L., Negro, A., et al. (2004). Protective effect of TAT-delivered a-synuclein: relevance of the C-terminal domain and involvement of HSP70. FASEB J 18, 1713–1715. Allende-Vega, N., & Saville, M. K. (2010). Targeting the ubiquitin–proteasome system to activate wild-type p53 for cancer therapy. Semin Cancer Biol 20, 29–39.

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