251

REVIEW

Neuroprotective effects of the Alzheimer’s disease-related gene seladin-1

Alessandro Peri and Mario Serio Endocrine Unit, Department of Clinical Physiopathology, Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic

Disorders for the Development of Novel Therapies (DENOThe), University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy

(Correspondence should be addressed to A Peri; Email: [email protected]fi.it)

Abstract

The endocrine and the nervous system are closely correlated throughout life, starting from the embryo and until the late stages of life. Alzheimer’s disease (AD) is the most common neurodegenerative disease associated with ageing. Unfortunately, an effective way to prevent or to cure this disease does not exist, so far. There is evidence that estrogens exert neuroprotective properties, although their efficacy against AD is still a matter of debate. In 2000 a new neuroprotective gene, i.e. seladin-1 (for SELective AD INdicator-1) was identified and found to be down regulated in AD vulnerable brain regions. Seladin-1 inhibits the activation of caspase-3, a key modulator of apoptosis. This protein has also enzymatic activity. In fact, it has been demonstrated that the seladin-1 gene encodes 3-b-hydroxysterol D-24-reductase, which catalyzes the synthesis of cholesterol from desmosterol. In recent years, it has been demonstrated that an appropriate amount of membrane cholesterol determines the generation of a barrier against toxic insults and prevents the production of b-amyloid, the histopathological hallmark of AD. This review will summarize the studies that have been focused on the characterization of the biological properties of seladin-1 since its first identification. In particular, the relationship between seladin-1-mediated neuroprotection and estrogens, IGF1 and thyroid hormones, will be described and discussed. Journal of Molecular Endocrinology (2008) 41, 251–261

Introduction The identification and characterization of seladin-1 A tight interplay between the endocrine and the nervous system occurs throughout life, starting from the embryo. The seladin-1 gene was first identified in 2000 by using a Hormones play a role in promoting brain development differential mRNA display approach to identify genes that at the beginning of life and contribute to maintain brain were differentially expressed in selective vulnerable brain homeostasis until the senile age. With regard to the latter regions in AD (Greeve et al. 2000), such as the issue, although the neuroprotective role of estrogen is hippocampus, the amygdala, the inferior temporal cortex well established, their usefulness in preventing or and the entorhinal cortex (Selkoe 2001). Among the over treating the most common neurodegenerative disease 30 genes differentially expressed in AD vulnerable brain associated with ageing, i.e. Alzheimer’s disease (AD), regions versus unaffected areas, the authors identified a is still a debated question. The identification of the novel cDNA (thereafter named seladin-1)withamarkedly seladin-1 (SELective AD INdicator-1) gene as a novel reduced expression in the inferior temporal cortex of AD neuroprotective factor opened a new scenario on the patients compared with the frontal cortex, obtained complex molecular network involving the endocrine shortly postmortem. Conversely, seladin-1 was evenly and the nervous system. Seladin-1 is the human homolog expressed in the brain of unaffected individuals. Later of the plant DIMINUTO/DWARF1 gene, primarily on, we demonstrated that this gene is abundantly described in Arabidopsis thaliana (Takahashi et al. 1995, expressed in stem cells, whereas the level of expression Klahre et al. 1998). This review will summarize the markedly decreases when these cells are induced to experimental data obtained in the last few years differentiate into mature neurons (Benvenuti et al.2006). regarding the characterization of the biological proper- This finding led us to hypothesize that defective seladin-1 ties of seladin-1 and the relationship of this protein with expression detected in AD vulnerable brain regions the endocrine system. might be linked to an impaired neuronal stem cell

Journal of Molecular Endocrinology (2008) 41, 251–261 DOI: 10.1677/JME-08-0071 0952–5041/08/041–251 q 2008 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org

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compartment, that could be a potential risk factor to suggesting a ROS-scavenging activity for this protein. This develop this disease. The seladin-1 gene (GenBank hypothesis was validated by the observation that intact accession number AF261758) spans 46.4 kb, maps to seladin-1 was associated with high H2O2-scavenging chromosome 1p31.1–p33, and comprises nine exons and activity, whereas an N-terminal deletion caused the loss eight introns; it encodes an open reading frame of 516 of this activity. Although the literature unequivocally amino acid residues. Seladin-1 is located in the recognizes the anti-apoptotic property of seladin-1, one endoplasmic reticulum and, although to a lesser extent, single study addressed this protein as a key mediator of in the Golgi apparatus (Greeve et al.2000). Ras-induced senescence (Wu et al.2004). In this study it Apart from the brain, seladin-1 expression has been was shown that, following oncogenic and oxidative stress, also detected in many different organs, including seladin-1 binds p53 in fibroblasts and displaces E3 endocrine organs, such as the adrenal gland (Greeve ubiquitin ligase Mdm2 from p53, thus resulting in p53 et al. 2000, Sarkar et al. 2001, Luciani et al. 2004, Battista accumulation. Ablation of seladin-1 caused the bypass of et al. 2007), the pituitary gland (Greeve et al. 2000, Ras-induced senescence, and allowed Ras to transform Luciani et al. 2005), the thyroid gland (Greeve et al. cells. Wild-type seladin-1 cells, but not mutants that 2000), the prostate (Dong et al. 2005, Hendriksen et al. disrupt its association with either p53 or Mdm2, were able 2006, Biancolella et al. 2007, Bonaccorsi et al. 2008), the to suppress the transformed phenotype. These results ovary (Greeve et al. 2000, Fuller et al. 2005), and the showed an unanticipated role for seladin-1 in integrating testis (Greeve et al. 2000). cellular response to oncogenic and oxidative stress. A very With regard to its biological effects, seladin-1 was recent publication has possibly clarified the apparent originally found to confer resistance against b-amyloid discrepancy between the role of seladin-1 in preventing and oxidative stress-induced apoptosis and to effectively apoptosis on the one hand, and its association with inhibit the activation of caspase-3, a key mediator of the increased levels of p53 on the otherhand. Neuroblastoma apoptotic process. Interestingly, in PC12 cells (rat adrenal cells were subjected to acute or chronic oxidative stress. pheochromocytoma) that were selected for resistance Following acute stress, seladin-1 expression increased against b-amyloid toxicity, the level of expression of and the over expression conferred resistance to H2O2- seladin-1 was remarkably high (Greeve et al.2000). A induced toxicity. Conversely, chronic exposure to subsequent study demonstrated that the down-regulation oxidative stress diminished the expression of seladin-1, of seladin-1 expression in vulnerable AD brain areas is but the protective effect was maintained. In fact, reduced paralleled by an increase in the amount of hyper- seladin-1 levels prevented apoptosis in a p53-dependent phosphorylated tau, a protein component of neuro- manner, via increased p53 ubiquitination and fibrillary tangles (Iivonen et al.2002). The anti-apoptotic degradation (Kuehnle et al. 2008). effect of seladin-1 has also been associated to a more aggressive behavior and to a defective response to pharmacological treatment in human neoplasia. For Seladin-1 as an enzyme instance, in pituitary tumors we have detected markedly higher levels of expression of seladin-1 in non-function- A fundamental step forward in unraveling the biological ing adenomas compared with GH-secreting adenomas. properties of seladin-1 was represented by the demon- Accordingly, the somatostatin analogue octreotide was stration that this protein has also a specific enzymatic able to activate caspase-3 and to induce apoptosis in activity, which was found to be markedly reduced in primary cell cultures obtained from GH-secreting adeno- desmosterolosis, a rare autosomal recessive disorder mas, but not from non-functioning adenomas (Luciani characterized by multiple congenital anomalies (FitzPa- et al.2005). Our conclusion was that seladin-1 may be trick et al.1998). Patients with desmosterolosis have viewed as one of the factors that confer resistance to elevated plasma levels of the cholesterol precursor pharmacological intervention in this subset of pituitary desmosterol and this abnormality suggested a deficiency tumors. In another study, higher levels of expression of oftheenzyme3-b-hydroxysterol D-24-reductase seladin-1 in melanoma metastases compared with (DHCR24), which catalyzes the reduction of the D24 primary tumors, were associated with resistance against double bond in desmosterol to produce cholesterol oxidative stress-induced apoptosis (Di Stasi et al.2005). (Fig. 1). Waterham and colleagues identified the human Very recently, it has been demonstrated that the ability of DHCR24 cDNA, which appeared identical to seladin-1 seladin-1 to protect against apoptosis elicited by oxidative (Waterham et al.2001). DHCR24 activity was confirmed stress may be related to the scavenger activity of this in vitro by enzymatic assay following heterologous protein (Lu et al.2008). The authors of the study showed expression of the DHCR24 cDNA in Saccharomyces that intracellular generation of reactive oxygen species cerevisiae. Conversely, in constructs containing mutant (ROS) in response to H2O2 was diminished in embryonic DHCR24 alleles from patients with desmosterolosis the mouse fibroblasts expressing seladin-1, compared with conversion from desmosterol into cholesterol was absent cells in which the expression had been abolished, thus or markedly reduced. Desmosterolosis belongs to a group

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Figure 1 Cholesterol biosynthesis from squalene. Deficiencies of the circled enzymes are responsible for different inherited disorders of cholesterol biosynthesis. DHCR24, 3b-hydroxysterol D24-reductase 14 (desmosterolosis); SC14DM, 3b-hydroxysterol C14 demethylase; DHCR14, 3b-hydroxysterol D -reductase (Greenberg skeletal dysplasia); SC4DM, 3b-hydroxysterol C4 demethylase complex (including a 3b- hydroxysteroid dehydrogenase defective in CHILD syndrome); SD8O7I, 3b-hydroxysterol D8–D7 isomerase (Conradi Hunermann syndrome); SD5DS, 3b-hydroxysterol D5-desaturase (lathosterolosis); and DHCR7, 3b-hydroxysterol D7-reductase (Smith–Lemli–Opiz syndrome). Modified from Peri et al.(2005). of several inherited disorders, linked to enzyme defects characterized by major developmental malformations in the cholesterol biosynthetic pathway at the post- and in most cases determine severe neuropsychological squalene level, which have been described in recent alterations, suggesting an important role for cholesterol years (Herman 2003). These genetic diseases are in brain homeostasis. www.endocrinology-journals.org Journal of Molecular Endocrinology (2008) 41, 251–261

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Interestingly, the DIMINUTO/DWARF1 gene, the that the central nervous system contains as much as plant homolog of seladin-1, encodes an enzyme involved 25% of the total amount of unesterified cholesterol in in the biosynthetic pathway of the most active the entire body, which is mostly produced via local de brassinosteroid, brassinolide (Klahre et al. 1998). novo synthesis. Keeping this in mind, it is not surprising Brassinosteroids are a class of sterols plant hormones that several studies pointed out the fact that the that can be considered as the counterpart of animal intracellular content of cholesterol, particularly the steroid hormones. They regulate gene expression, amount contained in the cell membrane, should stimulate cell division and differentiation, modulate be addressed much more than the plasma levels reproductive biology and promote cell elongation (Yanagisawa 2002). In this new scenario, the dichotomy (Clouse & Sasse 1998). Accordingly, DIMINUTO/ between the view of cholesterol as a neurotoxic or a DWARF1 mutants showed a reduced height compared neuroprotective factor might thus be only apparent. If with the wild-type plant, due a severe reduction in cell cell cholesterol is considered, an appropriate amount length (Takahashi et al. 1995). in the cell membrane would create a barrier against The identification of the 34 allelic variant of the toxic insults, whereas a cholesterol-depleted membrane apolipoprotein E as a major genetic risk factor for AD would ease the interaction with toxic factors such as suggests a role for cholesterol in the pathogenesis of b-amyloid, which may generate for instance an anom- this disease, although this is still an open and alous number of calcium channels leading to the controversial issue, at present. The published literature accumulation of toxic levels of calcium (Fig. 2; Arispe is divided between those who support the idea that & Doh 2002). Accordingly, reduced membrane lipids in cholesterol may favor the onset of the disease and those the cortex of AD transgenic mice have been detected who, on the contrary, believe that cholesterol may play a (Yao et al.2008). We have very recently provided protective role against AD. In particular, on the one evidence that over expression of seladin-1, as well as hand some reports showed that elevated cholesterol PEG-cholesterol treatment, increases resistance to levels increase b-amyloid formation in in vitro systems b-amyloid toxicity and prevents calcium influx in and in animal models of AD (Yanagisawa 2002, Herman neuroblastoma cells, whereas the exposure to a 2003, Puglielli et al. 2003). Accordingly, epidemiologi- selective inhibitor of DHCR24 blunts these effects, cal studies suggest that statin therapy may provide similarly to cholesterol depletion with methyl-b-cyclo- protection against AD, although the clinical benefit of dextrin (Cecchi et al. 2008). The amount of cell statins might be also due to their cholesterol-indepen- cholesterol may also affect amyloidogenesis. It has dent effects on cerebral circulation and inflammation been shown that in membranes from AD patients, or (Reiss et al. 2004). Furthermore, it has to be said that in rodent hippocampal neurons with a moderate most of the commercially available statins do not cross reduction of membrane cholesterol, the interaction the blood–brain barrier. This observation appears to be between the amyloidogenic enzyme b-secretase and in agreement with the opinion of those who, on the amyloid precursor protein (APP) is facilitated, thus other hand, support the idea that cholesterol may leading to elevated production of b-amyloid (Fig. 3; actually be good for the brain. It has to be considered Abad-Rodriguez et al. 2004). Similarly, seladin-1

Figure 2 Interaction between b-amyloid and the cell membrane. In the presence of reduced membrane cholesterol, the insertion of b-amyloid is eased by the fluidity of the membrane (left). Thus, b-amyloid C generates open channels through which Ca2 ions flow across the membrane is allowed. Conversely, the b-amyloid insertion process is prevented by the stiffness of a cholesterol-enriched membrane (right). From Arispe & Doh (2002), modified.

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contained virtually no cholesterol, whereas desmosterol accumulation was observed. These animals were C C around 25% smaller in size than DHCR24 / and C K DHCR24 / littermates at birth. In contrast to initial reports, it was subsequently demonstrated that these animals do not survive until adulthood: in fact, they show a lethal dermopathy at birth, associated with retention of epidermal water in agreement with similar observations in patients with desmosterolosis, and die within a few hours (Mirza et al. 2006, 2008).

Seladin-1 as a new effector of estrogen receptor (ER)-mediated neuroprotection

There is well established in vitro evidence that estrogens exert neurotropic and neuroprotective effects by stimulating the expression of neurotropins and cell- survival factors, enhancing synaptic plasticity, and acting as an antioxidant factor (Behl 2003, Maggi et al. 2004, Turgeon et al. 2006). AD is more common in women and it is known that decreased estrogen levels after menopause are a risk factor for the disease (Paganini-Hill & Henderson 1994). Thus, estrogen therapy has been considered a rationale option for the treatment of this disease. Despite the lack of general Figure 3 Relationship between membrane cholesterol and consensus, several studies indicated that estrogen b-amyloid production. (A) In healthy subjects the stiffness of the treatment may decrease the risk or delay the onset of membrane prevents the interaction between b-secretase and amyloid precursor protein (APP), thus inhibiting the synthesis of AD in post-menopausal women (Fillit 2002). Although b-amyloid. (B) In AD patients, as well as in neurons with a the data from the Women’s Health Initiative Memory moderate reduction of membrane cholesterol, the fluidity of the Study trial indicated that hormone replacement cell membrane facilitates the interaction between b-secretase and therapy (HRT) has no benefit (Rapp et al. 2003, APP, thus resulting in an elevated production of b-amyloid. Shumaker et al. 2003), it has to be considered that a number of factors may determine the efficacy of estrogens or HRT, such as age, the menopausal status, deficient mouse brains had reduced levels of choles- the route of administration and the dose, the starting terol, that were associated with increased cleavage of cognitive function, and the presence of pre-existing risk APP by b-secretase and high levels of b-amyloid. factors (i.e. smoking, apolipoprotein E genotype; Conversely, seladin-1 over expression increased choles- MacLusky 2004, Turgeon et al. 2006). In particular, terol levels and reduced APP processing in neuroblas- there seems to be a critical time for estrogen treatment. toma cells (Crameri et al. 2006). These results suggest In fact, early and prolonged therapy has been found to that loss of membrane cholesterol in neurons contri- produce the maximum benefit in terms of reduced risk butes both to increased membrane interaction with for AD (Resnick & Henderson 2002, Zandi et al. 2002). b-amyloid and to excessive amyloidogenesis in AD. In addition, estrogen therapy is not the same as HRT Thus, the reduced expression of seladin-1 in AD and the type of progestogen used may determine the vulnerable regions is in keeping with the ‘membrane outcome of the therapeutic intervention (Schumacher integrity’ theory. Overall, the experimental findings on et al. 2007). The neuroprotective role of the selective ER the neuroprotective role of seladin-1 are clearly in favor modulators (SERMs) has been less extensively investi- of the hypothesis that an optimal amount of cell gated. Nonetheless, a neuroprotective effect of tamoxi- cholesterol may be critical for brain homeostasis. In fen and raloxifene has been observed (Dhandapani & this view, the role of statins in neuroprotective strategies Brann 2002) and a beneficial role of tamoxifen and might be limited to their vasoprotective and/or anti- raloxifene against b-amyloid toxicity has been demon- inflammatory effects. strated in rat neurons (O’Neill et al. 2004a,b). The Mice with a targeted disruption of the DHCR24 gene Multiple Outcomes of Raloxifene Evaluation trial have been generated (Wechsler et al. 2003). As evaluated the cognitive function in more than 5000 K K expected, plasma and tissues of DHCR24 / mice women with osteoporosis who were assigned to receive www.endocrinology-journals.org Journal of Molecular Endocrinology (2008) 41, 251–261

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raloxifene (60 mg or 120 mg) or placebo daily for 3 Noteworthy, this hypothesis was supported by an years. Compared with those taking placebo, women additional very recent study. In fact, we demonstrated receiving 120 mg/day of raloxifene had a 33% lower risk that, upon silencing seladin-1 expression by small of mild cognitive impairment and somewhat lower risks interfering RNA (siRNA) methodology, the protective of AD and any cognitive impairment (Yaffe et al. 2005). effect against b-amyloid and oxidative stress toxicity In order to establish whether seladin-1 may be exerted by 17b-estradiol was lost (Fig. 4). The - involved in estrogen-mediated neuroprotection, we specificity of these results was validated by the have taken advantage of a unique cell model of observation that in cells exposed to control siRNA human fetal neuronal precursor, that expresses both the protective effects of 17b-estradiol were maintained ER a and b (Barni et al. 1999). These fetal neuroe- (Luciani et al. 2008). Furthermore, a computer assisted pithelial cells (FNC) are long-term cell cultures from analysis revealed the presence of half-palindromic human fetal (8–12 weeks of gestational age) olfactory estrogen responsive elements (EREs) upstream of the epithelium, that were established, cloned and propa- coding region of the seladin-1 gene. A region spanning gated by Vannelli et al. (1995). FNC cells express both around 1500 bp was cloned in a luciferase reporter neuronal and olfactory markers that are typical of vector, which was transiently co-transfected with the ER maturing olfactory receptor neurons, are electrically a in CHO cells. The exposure to 17b-estradiol, as well excitable and following exposure to a number of different aromatic chemicals show a specific increase in intracellular cAMP, indicating some degree of functional maturity (Vannelli et al. 1995). Thus, FNC cells appear to originate from the stem cell compart- ment that generates mature olfactory receptor neurons. Preliminarily, we confirmed the protective role of estrogens/SERMs in the brain. In fact, 17b-estradiol was able to stimulate cell proliferation (100 pM and 100 nM) and to effectively counteract b-amyloid- and H2O2-mediated toxicity (100 pM, 1-10-100 nM; Benve- nuti et al. 2005). In agreement with 17b-estradiol, also the SERM tamoxifen (100 pM–100 nM) effectively protected FNC cells from the toxic effects of b-amyloid, whereas partially different results were observed with raloxifene. In fact, cell viability after exposure to b-amyloid was preserved at low concen- trations of raloxifene (100 pM and 1 nM). Conversely, 10 and 100 nM did not exert protective effects. In addition, we demonstrated that the protective action of estrogens in FNC cells was associated with a counteracting effect against b-amyloid-induced apop- tosis, as demonstrated by the strong inhibition of the activation of caspase-3. In the same study, we also demonstrated that FNC cells constitutively express seladin-1 and that 17b-estradiol (10 pM–100 nM), tamoxifen (1 nM), raloxifene (1 nM), and a selective ERa agonist (propylpyrazole-triol; 10 nM) significantly increased the amount of mRNA. However, a selective ERb agonist (diarylpropionitrile; 10 nM) did not affect seladin-1 expression, whereas higher concen- Figure 4 (A) Effect of 17b-estradiol (E2; 10 nM for 48 h) against trations of raloxifene (10–100 nM) determined a b-amyloid (BA; 100 nM for 18 h) toxicity in FNC (white columns) or in FNC cells subjected to seladin-1-specific siRNA (grey marked reduction. These findings, and in particular columns). (B) Effect of 17b-estradiol (10 nM for 48 h) against the parallelism between the concentrations of ralox- oxidative stress (200 mMH2O2 for 20 h) in FNC (white columns) ifene that conferred neuroprotection on the one or in FNC cells subjected to seladin-1-specific siRNA (grey G hand, and stimulated seladin-1 expression on the columns). The results were expressed as mean percentage S.E.M. of viable cells/well in three different experiments. *P!0.05 other hand, led us to hypothesize that seladin-1 might versus the corresponding untreated control cells; #ZP!0.05 be a mediator of the neuroprotective effects of versus the corresponding cells exposed to b-amyloid (A) or to estrogens/SERMs. H2O2 (B). Modified from Luciani et al. (2008).

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Downloaded from Bioscientifica.com at 09/27/2021 11:10:28AM via free access Seladin-1 and neuroprotection . A PERI and M SERIO 257 as to raloxifene and tamoxifen increased luciferase activity, thus suggesting a functional role for the half EREs of the seladin-1 gene. Overall, these additional data provided a direct demonstration that seladin-1 is a fundamental mediator of the neuroprotective effects of estrogens.

Seladin-1 as a mediator of the pro- survival effects of IGF1

There is strong evidence that the insulin-like growth Figure 5 Model representing the working hypothesis on the factor (IGF) system plays an important role in the relationship between seladin-1, estrogens and IGF1. The cartoon depicts a neuroblast, according to the cell model in which the nervous system by favoring for instance neuronal experimental studies regarding this issue were performed by our development, metabolism, survival, and regeneration group. 17b-estradiol (E2) stimulates the expression of the seladin- (Matthews & Feldman 1996, Russo et al. 2004, 2005, 1 gene via a functionally active half-palindromic ERE present in its Mendez et al. 2005). Conversely, high glucose concen- promoter region. In addition, 17b-estradiol increases the release of IGF1. IGF1, on turn, binds to IGF1 receptors (IGF1R) and trations may be detrimental to nerves and it is generally stimulates the expression of seladin-1, too. The dotted lines accepted that one of the mechanisms leading to suggest that the latter might be a direct effect or it might be diabetic neuropathy may be related to a direct or an mediated via an interaction between IGF1R and ER. indirect effect of glucose levels. Glucose may cause a number of alterations in nervous cells, including for instance altered transcription and translation, ion alternatively), but not constant (20 mM), high glucose channel dysfunction, altered axonal transport, demye- concentrations significantly reduced FNC cell growth, lination, AGE formation and impaired neurotrophic increased apoptosis and disrupted the IGF system, as support (Tomlinson & Gardiner 2008). There is demonstrated by the marked reduction of IGF1 and evidence that intermittent high glucose concentrations, IGFBP2 release. The addition of IGF1 to the culture as it may occur in poorly controlled diabetes, may be medium counteracted the effects of intermittent high more detrimental to cells than constant high glucose, as glucose on cell proliferation and apoptosis. Interest- observed in endothelial, mesangial, renal tubular cells ingly, we found that IGF1 significantly increased and fibroblasts (Piconi et al. 2006). However, no seladin-1 expression, whereas high glucose markedly previous study had assessed the effect of intermittent reduced it. Finally, 17b-estradiol (10 nM) treatment high glucose on i) neuronal cell growth and on ii) the determined a ninefold increase of the release of IGF1 in IGF system. Furthermore, there are no reports regard- the culture medium, indicating that a cross-talk ing a possible relationship between the IGF system and between estrogens and IGF1 occurs in FNC cells. seladin-1. In view of the reported evidence of a tight Overall, these results suggest that seladin-1 might be a link between estrogens and the IGF family in the mediator of the pro-survival effects of IGF1 in the nervous system in terms of neuronal cell differentiation, nervous system, although the exact mechanism of survival and regeneration (Mendez et al. 2005, 2006), we reasoned that a relationship between seladin-1 and the action needs to be addressed in future studies, designed IGF1 system might occur, similar to the previously for instance to evaluate the effects of IGF1 and high demonstrated association between seladin-1 and estro- glucose after silencing seladin-1 expression. In gens. Thus, very recently we have addressed these issues addition, these findings indicate that the disruption using again FNC as the in vitro cell model. We of the IGF system may be one of the mechanisms demonstrated that these cells express IGF1 receptor through which glucose toxicity causes diabetic neuro- (IGF1R) and synthesize and release in the culture pathy. An interplay between seladin-1, estrogens and medium IGF1, IGFBP2 and -4, but not -1, -3, -5 and -6 IGF1 may also be envisaged. In particular, both IGF1 (Giannini et al. 2008).TheexposuretoIGF1 and 17b-estradiol directly stimulate the expression of (1–100 nM) stimulated cell growth, reduced apoptosis this neuroprotective factor; furthermore, the latter and increased the release of IGFBP2, whereas it hormone appears to have also an indirect stimulatory decreased the amount of IGFBP4. It is known that effect, by increasing the release of IGF1, which on turn IGFBP2 may facilitate the binding of IGF1 to its can bind to IGF1R via an autocrine loop (Fig. 5). It receptor (Brooker et al. 2000), whereas IGFBP4 is remains to be elucidated whether IGF1-induced generally considered as a potent inhibitor of the seladin-1 expression is a direct consequence of IGF1/ biological effects of IGF1 (Mazerbourg et al. 2004). IGF1R binding or is mediated via an interaction Conversely, intermittent (20 mM or 10 mM, between IGF1R and ER. www.endocrinology-journals.org Journal of Molecular Endocrinology (2008) 41, 251–261

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Figure 6 Effect of T3 and T4 on the amount of seladin-1 mRNA levels in FNC, hMSC and hMSC-derived neurons (hMSC-n), as assessed by real-time RT-PCR. *P!0.05 versus untreated cells (C). From Benvenuti et al. (2008), modified.

Seladin-1 as a mediator of the effects of differentiation into a neuronal phenotype, as assessed by thyroid hormones (TH) in promoting brain morphological, immunocytochemical and electro- development physiological evidence (Benvenuti et al. 2008). In addition, T3, and to a lesser extent T4, significantly It is well known that TH play a fundamental role during increased the expression of seladin-1 in both cell types fetal life, particularly in promoting brain development. and effectively counteracted camptothecin-induced TH affect the expression of genes, that are related, for apoptosis. However, in hMSC that had been differen- instance, to cell migration (i.e. reelin, laminin, tenascin tiated into mature neurons (hMSC-n), the expression of C), myelination (i.e. myelin basic protein, proteolipid seladin-1 was significantly lower than in undifferentiated protein, myelin associated glycoprotein) and neuronal cells and was not affected by TH (Fig. 6). This finding is differentiation (i.e. nerve growth factor (NGF), brain- in keeping with similar observations from in vivo studies derived neurotropic factor (BDNF); Ko¨nig & Neto 2002, performed in experimental animals showing that most Santisteban & Bernal 2005). Accordingly, it has been of the TH-regulated genes are responsive only during a shown that early maternal hypothyroxinemia alters fetal limited time interval of brain development (Ko¨nig & brain histogenesis and cytoarchitecture in rats (Lava- Neto 2002). The biological role played by the increased do-Autric et al. 2003), and unrecognized hypothyroidism expression of seladin-1 induced by TH in neuronal in women in the first trimester of pregnancy may precursors remains to be fully elucidated and additional adversely affect the neuropsychological development of the progeny (Haddow et al. 1999, Pop et al. 2003, Morreale de Escobar et al. 2004). There is also evidence both in embryonic and adult mammals supporting a key role of TH in the development and maintenance of basal forebrain cholinergic neurons typically involved in AD (Patel et al. 1987, Calza` et al. 1997). Therefore, we hypothesized that seladin-1 might be a mediator of the effects of TH in the brain. In particular, we addressed the potential role of this factor during the development of the nervous system. To this purpose we used FNC cells and human mesenchymal stem cells (hMSC) as cell models representing neuronal precursors. The choice of hMSC was based on the fact that these cells, that are much more easily obtainable than neuronal stem cells, Figure 7 Model representing the hypothesized role of seladin-1 during brain development. TH stimulates the expression of may be readily differentiated into neurons (Woodbury seladin-1, that may contribute to maintainenance of a pool of et al. 2000, Sanchez-Ramos 2002, Benvenuti et al. 2006). undifferentiated and self-renewing neuronal precursors. In We first demonstrated that both FNC and hMSC express addition, TH induces the expression of genes, that promotes the TH receptors and that T3 was able to promote the differentiation of neuronal precursors into mature neurons.

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Downloaded from Bioscientifica.com at 09/27/2021 11:10:28AM via free access Seladin-1 and neuroprotection . A PERI and M SERIO 259 studies performed, for instance, in seladin-1 ‘silenced’ Fabiana Rosati, Matteo Morello, Francesca Dichiara, Corinna Giuliani, cells, will probably provide an answer to this question. Stefano Giannini, and Anna Pezzatini. The support provided by colleagues at the Department of Anatomy, Histology, and Forensic However, bearing in mind the well established anti- Medicine, the Department of Biochemical Sciences, the Department apoptotic activity of seladin-1, we hypothesized that one of Physiological Sciences, the Department of Haematology, the of the functions associated with the increased seladin-1 Institute of Dermatology and Venereology at the University of levels in the developing brain may be to protect Florence and at the Careggi University Hospital, Florence, and the neuronal precursor cells from death. From this point continuative collaboration with the Institute of Endocrine Sciences and the Laboratory of Developmental Neuroendocrinology, Depart- of view, seladin-1 might therefore be regarded as a factor, ment of Endocrinology, Centre of Excellence on Neurodegenerative which helps in maintaining a pool of young and Diseases, University of Milan, and the Department of Endocrinology self–renewing multipotent cells, to be then made and Metabolism, University of Pisa are also acknowledged. The available to other TH-regulated genes, which are able authors wish to thank Eli Lilly for kindly providing raloxifene. to promote the differentiation toward a neuronal phenotype (Fig. 7). 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