REVIEW Neuroprotective Effects of the Alzheimer's Disease-Related Gene Seladin-1

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 Downloaded from Bioscientifica.com at 09/27/2021 11:10:28AM via free access 252 A PERI and M SERIO . Seladin-1 and neuroprotection 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

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