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Keywords:

  • Alzheimer's disease;
  • epilepsy;
  • glutathione;
  • glutathione peroxidase;
  • Huntington's disease;
  • Parkinson's disease;
  • phospholipid hydroperoxide glutathione peroxidase;
  • selenium;
  • selenoprotein;
  • thioredoxin reductase

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Alzheimer's Disease
  5. Parkinson's Disease
  6. Huntington's Disease
  7. Epilepsy
  8. Concluding Remarks
  9. Acknowledgements
  10. REFERENCES

Selenoproteins are important for normal brain function, and decreased function of selenoproteins can lead to impaired cognitive function and neurological disorders. This review examines the possible roles of selenoproteins in Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and epilepsy. Selenium deficiency is associated with cognitive decline, and selenoproteins may be helpful in preventing neurodegeneration in AD. PD is associated with impaired function of glutathione peroxidase selenoenzymes. In HD, selenium deters lipid peroxidation by increasing specific glutathione peroxidases. Selenium deficiency increases risk of seizures in epilepsy, whereas supplementation may help to alleviate seizures. Further studies on the mechanisms of selenoprotein function will increase our understanding of how selenium and selenoproteins can be used in treatment and prevention of brain disorders. © 2014 IUBMB Life, 66(4):229–239, 2014


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Alzheimer's Disease
  5. Parkinson's Disease
  6. Huntington's Disease
  7. Epilepsy
  8. Concluding Remarks
  9. Acknowledgements
  10. REFERENCES

Selenium

The element selenium is essential for many organisms, including humans, and plays a role in a variety of physiological responses [1-3]. The selenium used by the human body is gained through various forms found in food and water including selenite, selenate, selenocysteine, and selenomethionine [4]. The bioavailability of selenomethionine has been shown to be greater than selenite and selenate in mouse and human studies, and is likely to be the main source of selenium for living organisms [5, 6]. The selenium content in foods varies considerably. Fruits and vegetables contain trace amounts of the element, while cereal, legumes, and meat are rich sources of the selenium in the form of selenomethionine [7]. Selenium food content is often dependent upon regional soil selenium content. This can vary from levels toxic to livestock to selenium-replete regions where humans suffer from health problems from selenium deficiency [8].

To maintain a selenium balance of zero (where selenium intake equals selenium excretion in urine and feces), the required intake for men is 80 µg/day and women 57 µg/day [9]. The US recommended daily allowance (RDA) for selenium is 55 µg/day [10]. The mean selenium intake in United States is 93 µg per day in women and 134 µg per day for men [11]. Although Se intake overall in the US and North America may be adequate, Europeans have a mean intake of only 40 µg per day [11]. Se intake within the US also varies demographically, with poor African Americans having significantly lower blood levels of Se than poor whites, and may be at greater risk for health problems from low selenium [12].

The tolerable intake level (UL) is 400 µg/day, with selenosis being an adverse reaction at higher levels [7]. Thus, the balance of selenium in the body is critical because deficits can lead to neurological problems, cardiovascular problems, cancer, and immunological deficiencies, while higher levels result in toxicity [11].

Selenoprotein Synthesis

Dietary intake of organic and inorganic forms of selenium is converted to selenocysteine (Sec), the 21st amino acid [1]. Selenite and other inorganic selenium forms of selenium are converted to selenide via glutathione–glutaredoxin and thioredoxin pathways, while selenocysteine, selenomethionine, and other organic forms may require modification through β-lyase activity (i.e., Sec lyase) or trans-selenation (analogous to trans-sulfuration) [5]. Sec is unusual as its tRNA is encoded by the codon UGA, which is normally a stop codon. A specific stem-loop secondary structure at the 3′-end of the untranslated region of all selenoprotein mRNAs, termed the selenocysteine insertion sequence (SECIS) element, promotes read-though and the insertion of Sec at the UGA codon [1, 13]. Selenophosphate synthetase 2 (SPS2) converts selenide to monoselenophosphate, which is then used to modify a serine-conjugated tRNA to generate Sec-tRNA, used in selenoprotein production [14]. There are also a multitude of other factors involved in selenoprotein synthesis, including selenocysteine-specific elongation (EFsec), SECIS-interacting protein 2 (SBP2), secP43, and O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthetase (SepSecS) [1, 15].

Types of Selenoproteins

There are currently 25 known selenoproteins in the human proteome [16]. Information about brain function of selenoproteins is summarized in Table 1. The three well-studied subfamilies of selenoproteins include thioredoxin reductase (TrxR), glutathione peroxidase (GPx), and iodothyronine deiodinases (DIO). The thioredoxin reductases are members of the pyridine nucleotide-disulfide oxidoreductase family [17]. Three of these selenoproteins have been identified in mammals. These selenoproteins include TrxR1, which functions in the cytosol and nucleus, TrxR2, which functions in the mitochondria, and TrxR3, which functions in testis [18]. The TrxRs are also important components of the mechanism to reduce peroxide [1]. This group of selenoproteins is required for reduction of thioredoxin (Trx), which uses a cysteine thiol-disulfide exchange for reduction of thiol groups in protein residues [19, 20]. The Trx–TrxR systems are also important for reducing proteins that have cysteine in DNA-binding domains, which include NF-kB, AP-1, p53, and glucocorticoid receptors. Trx can inhibit apoptosis signaling regulating kinase 1 (ASK1) and prevent apoptosis to control cell division, longevity, and cell death [20].

Table 1. Selenoprotein function in the brain and involvement in brain disorders
SelenoproteinNormal function in brainBrain disorder involvement
Glutathione Peroxidase (GPx) Family Alzheimer's [21-23], Parkinson's [21, 24-27], epilepsy [21, 28], and Huntington's [29, 30]
GPx1Peroxide/ROS reduction [21]Alzheimer's [21], Parkinson's [21, 26], epilepsy [28], Huntington's [29, 30]
GPx4Reduction of phospholipid hydroperoxides [31]Alzheimer's [21, 23], Parkinson's [21, 24-27], epilepsy [21]
GPx6Undetermined peroxidase [32]Huntington's [29]
Thioredoxin Reductase (TrxR) Family Alzheimer's [21, 33] and epilepsy [21, 28]
TrxR1Reduction of hydrogen peroxide and oxidative stress [20], regulate redox-sensitive transcription factors that control cellular transcription mechanisms [20]epilepsy [28]
TrxR2Reduction of hydrogen peroxide and oxidative stress [20], regulate redox-sensitive transcription factors that control cellular transcription mechanisms [20] 
Deiodinase (DIO) Family  
DIO1Deiodination of T4 and T3 [34] 
DIO2Deiodination of T4 to reverse T3 & T3 to T2 [34] 
Selenoprotein H (SelH)Redox sensing, nuclear localization and DNA binding [35, 36] 
Selenoprotein K (SelK)ER stress response, calcium regulation, palmitoylation [37-39] 
Selenoprotein M (SelM)Unknown, ER protein, calcium regulation [3]Alzheimer's [40-43]
Selenoprotein P (Sepp1, SelP)Se retention within the brain [44]Alzheimer's [45-47], Parkinson's [21, 24, 48-50]
Selenoprotein S (SelS)Retrotranslocation of misfolded proteins from ER, ER stress response [51] 
Selenoprotein T (SelT)Unknown, ER protein, calcium regulation [52]epilepsy [53]
Selenoprotein W (SelW)Synaptic localization, staufen-2 interaction [54]epilepsy [28]
Methionine Sulfoxide B1 (MSRB1, SelR, SelX)Reduction of oxidized methionine residues, actin polymerization [55]Alzheimer's [56]

There are five GPx proteins in humans that are selenoproteins. These include the ubiquitous cytosolic GPx (GPx1), gastrointestinal GPx (GPx2), plasma GPx (GPx3), phospholipid hydroperoxides glutathione peroxidase (GPx4), and olfactory epithelium and embryonic tissue GPx (GPx6) [57]. GPxs use the antioxidant glutathione to reduce peroxides and other reactive oxygen species (ROS) that could potentially destroy cells and tissues [57, 58]. GPx1–3 are involved in the reduction of hydrogen peroxide and organic hydroperoxides, while GPx4 directly reduces phospholipids and cholesterol hydroperoxides [57]. GPx4 has an additional structural role in sperm maturation as an important component in the sperm's helical mitochondrial capsule that is responsible for sperm motility [59].

The deiodinases are involved in synthesis and metabolism of thyroid hormone [60]. Deiodinase 1 (DIO1) is located in the thyroid, liver, and kidney [61]. DIO2 is located in the thyroid, brain, pituitary, heart and skeletal muscle, and brown adipose tissue. DIO3 is located in the cerebral cortex and skin. DIO1 and DIO2 remove one of four iodines from T4 to convert it into active T3, while DIO1 and DIO3 can convert active T3 into inactive T2, and also can covert T4 into inactive reverse T3 [62].

Human selenoprotein P (Sepp1, or sometimes SelP) has 10 Sec residues, and acts as a selenium transporter [63]. Plasma Sepp1 transports selenium from the liver to other tissues, particularly to the brain and testes. Additionally, the N-terminal domain of Sepp1 has a thioredoxin domain for antioxidant function.

Other selenoproteins have diverse biological roles. Several selenoproteins are specific to the endoplasmic reticulum (ER). These include SelK, SelM, SelN, SelS, SelT, and Sep15 as well as DIO2 [64]. The ER selenoproteins SelK, SelS, and Sep15 are part of the unfolded protein response (UPR) and may have a role in reducing ER stress [37, 65, 66]. SelH is a nuclear localized DNA binding protein that plays a role in gene regulation [35, 36]. SelI is an ethanolamine phosphotransferase responsible for production of the membrane lipid phosphoethanolamine and subsequent sphingomyelins [67]. The enzyme methionine-R-sulfoxide reductase B (MSRB), also referred to as SelR or SelX, is responsible for reducing the R stereoisomer of methionine sulfoxide [68]. The functions of SelO and the testes-enriched SelV remain elusive [1, 16].

Selenium and Selenoproteins in Normal Brain Function

Human studies demonstrate the importance for selenium and selenoprotein synthesis for normal brain function. Selenium deficiency correlates with lower cognitive function and impaired motor function [69-72]. Impaired selenoprotein synthesis due to mutations in the SepSecS gene produces Progressive Cerebro-Cerebellar Atrophy (PCCA), an autosomal recessive disorder resulting in severe brain abnormalities [73]. PCCA is characterized by progressive microcephaly producing mental retardation and severe spasticity [74]. SepSecS is responsible for the step of selenocysteine synthesis on the Sec-tRNA, and is necessary for selenoprotein synthesis [75]. This emphasizes the importance of dietary selenium intake to maintain selenoprotein synthesis necessary for normal brain function.

Se has a general distribution in the body, but is maintained well in the brain. A study of rats fed a Se-deficient diet for 13 weeks demonstrated Se retention in the brain when plasma Se concentration was depleted [76]. This was also seen in a study of six generations of Se deficient rats, where more than 99% of Se concentration was reduced in the liver, blood, skeletal tissue, and muscle, but the brain retained 60% of its Se [77]. The retention of brain selenium may explain why selenium deficiency does not produce abnormalities as severe as those associated with selenoprotein synthesis disruption in PCCA.

Sepp1 plays a vital role in the homeostasis of Se in the brain [63]. Sepp1 knockout (KO) mice have decreased brain Se that is similar to that of wild-type animals raised on a 0 Se diet and Sepp1 knockout (KO) mice have a similar decrease of Se in the cortex, midbrain, brain stem, and cerebellum, while Se in the hippocampus is decreased by Sepp1 gene deletion but not by 0 Se diet [44]. Thus, Sepp1 is important for Se retention within the brain. Changes in Sepp1 may be involved in neurodegenerative disorders such as Alzheimer's [45-47] and Parkinson's [21, 24, 48-50].

GPx 1 and 4 are major forms of the GPx in the brain. GPx1 is a ROS scavenger that is expressed in both neurons and astrocytes [21]. GPx4 functions in various locations of the neuron including the cytosol, mitochondria, and nucleus. It destroys phospholipid hydroperoxides [31], and can work with vitamin E to suppress lipid peroxidation in various cell membranes and lipoproteins [78]. The GPx family has a potential role in diseases such as Parkinson's [21, 24-27], Alzheimer's [21-23], epilepsy [21, 28], and Huntington's [29, 30].

The TrxRs involved in brain function are primarily TrxR1 and TrxR2. They reduce hydrogen peroxide and oxidative stress as well as regulate redox-sensitive transcription factors that control cellular transcription mechanisms [20]. This protein family may have a protective roll in Alzheimer's [21, 33] and epilepsy [21, 28].

Two members of the DIO family have brain functions. DIO2 is mainly found in glial cells and it deiodinates T4 and T3. DIO3 functions in neuronal cells and it causes the deiodination of T4 to reverse T3 and T3 to T2 [34]. The role that this family of selenoproteins has in neurodegenerative diseases is currently unknown.

SelW has been shown to protect glial cells against oxidative stress caused by heavy metals and 2,2′-Azobis (2-amidinopropanel dihydrochloride [AAPH]) in rat models [79]. Studies have suggested that this selenoprotein is involved in reducing Alzheimer's [80] and epilepsy pathology [28]. SelH is a nuclear DNA binding protein that may upregulate antioxidant pathways [26, 35].

Further exploration is required to determine aspects of Se and selenoprotein involvement in the aging brain. The neurological disorders covered in this review and relevant selenoproteins are listed in Table 2.

Table 2. Summary of neurological disorder characteristics
Neurologic diseaseAlzheimer's disease [81, 82]Parkinson's disease [81, 83]Huntington disease [81, 84]Epilepsy [85, 86]
Key Clinical Features -Most common cause of dementia in elderly -Slow progression -Impaired intellectual function -Altered mood and behavior -Disorientation, memory loss and severe cortical dysfunction -Slow voluntary movement -Decreased facial expression -Hunched posture -Increased rigidity -Tremor at rest -Short accelerated steps (festinating gait) -Autonomic nerve dysfunction -Cognitive impairment -Movement disorder (involuntary jerky movements of all body parts with writhing movements of extremities) -Cognitive impairment (forgetfulness, thought and affective disorders, severe dementia) -Uncontrolled brain activity-Impaired neurologic function -May include loss of consciousness, motor, sensory or autonomic symptoms
Neuropathologic features -Brain atrophy -A beta plaques (Neuritic and diffuse plaques) -Neurofibrillary tangles -Pallor of substantia nigra and locus ceruleus -Loss of pigmented, catecholaminergic neurons -Lewy bodies (cytoplasmic eosinophilic round inclusions with dense core surrounded by pale halo containing AS) -Atrophy of caudate nucleus and putamen -Dilated lateral and third ventricles. -Frontal lobe atrophy most prominent -Severe loss of neurons in caudate and putamen with gliosis -Intranuclear inclusions in caudate, putamen and cerebral cortex neurons (protein aggregates with huntingtin) -Infarcts -Postsurgical cavities -Brain neoplasms -Brain inflammatory conditions -Contusions -Brain developmental abnormalities (Cortical dysplasia, neuronal heterotopias, excess neurons in white matter) -Chaslin gliosis (subpial gliosis) -Cortical diffuse gliosis and neuronal loss -Hippocampal sclerosis
Genetics [87-90] -Early onset, autosomal dominant mutations: amyloid-precursor protein (APP), Presenilin 1, Presenilin 2. -Late onset, genetic risk factors: ApoE allele, BIN1, CLU, PICALM, and CR1 -Dominant: SNCA mutations, repeats -Autosomal dominant mutations: LRRK2 -Autosomal recessive mutations: Parkin, PINK1, DJ-1, ATP13A2 -Risk Factor: β-glucocerebrosidase (GBA) -Autosomal dominant mutation: Huntingtin (HTT) -Unknown
Selenoproteins (See Table 1) -GPx1 -GPx4 -SelM -Sepp1 -TrxR -MSRB1 -GPx1 -GPx4 -Sepp1 -SelT -TrxR1 -GPx1 -GPx6 -GPx1 -GPx4 -TRxR1 -SelW

Alzheimer's Disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Alzheimer's Disease
  5. Parkinson's Disease
  6. Huntington's Disease
  7. Epilepsy
  8. Concluding Remarks
  9. Acknowledgements
  10. REFERENCES

Pathophysiology of Alzheimer's Disease

There are various genetic and environmental risk factors for Alzheimer's disease (AD) [91]. Early-onset Alzheimer's disease can be caused by several autosomal dominant mutations within the amyloid-precursor protein (APP) gene and the presenilin (PS) 1, and 2 genes. Genetic variants of other genes, especially apolipoprotein E (ApoE), can increase risk of developing late-onset or sporadic AD. Certain environmental factors may also play a role in the pathogenesis and pathophysiology of AD, including certain metals, brain injuries, dietary deficiencies, pesticides, and infections [92].

AD is a progressive dementia defined by the presence of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs), observable upon histological examination of autopsied brain. Aβ is cleaved from amyloid precursor protein (APP) [93]. APP can be cleaved by gamma-secretase (γ-secretase) and alpha-secretase (α-secretase) to produce a soluble, non-amylogenic peptide. However, in AD, γ-secretase and beta-secretase (β-secretase) cleave APP to make the insoluble peptides Aβ40 and Aβ42, the main form of amyloid in neuritic plaques. Aβ plaques are primarily found in the cerebral cortex and hippocampus in AD, and eventually spread throughout the brain as the disease progresses [94].

NFTs result from hyperphosphorylation of tau proteins [95]. Tau proteins are closely associated with the microtubules in axons. In AD, hyperphosphorylated tau aggregates in the somatic-dendritic portion of the neuron, eventually forming NFTs [95]. Reversing the progression of Aβ plaques and NFTs has been central to recent research for AD treatments.

Selenium and Selenoprotein in relation to Alzheimer's Disease

Selenium deficiency correlates with impaired cognitive function [69-71]. Residents of rural areas of China that are deficient in soil selenium have reduced body levels of selenium, correlating with decreased cognitive ability [71]. Studies have found decreased selenium in individuals with Alzheimer's disease [96, 97]. Several studies have indicated that selenium may help prevent Alzheimer's pathology. Seleno-l-methionine combined with vitamin E protects against oxidative stress and toxicity from β-amyloid in cell culture [98]. This was also effective in reducing pathology in a mutant APP and presenilin Alzheimer's rodent model [99]. Injections of tricyclodecan-9-yl-xanthogenate (D609), a compound that mimics glutathione (GSH), decreased oxidative stress and Aβ toxicity by increasing activity of GPx [22]. Sodium selenite can inhibit amyloid production by decreasing gamma secretase activity [40, 100]. Selenite also mitigates pathology and cognitive impairment in a streptozotocin-induced rodent model of AD [101]. Alternatively, selenium deficiency increased AD pathology in a rodent AD model [102], and also by a reduction of phospholipid hydroperoxidase GPx4 [23]. Sodium selenate reduced neurofibrillary tangle formation, reportedly by acting as an agonist for protein phosphatase 2A (PP2A) [103, 104].

In human postmortem AD brain, Sepp1 was associated with both Aβ plaques and NFTs [45]. Knock down of Sepp1 using siRNA in N2A cells increased apoptosis and decreased viability in both untreated cells and cells exposed to amyloid toxicity [47]. Sepp1 knockout mice had impaired learning and deficient long-term potentiation (LTP), a physiological model for memory [46], demonstrating that Sepp1 is important for cognitive function. The role of Sepp1 in AD brain is not understood. The selenoprotein has shown to protect astrocytes from harmful effects of tert-butyl hydroperoxide (t-BHP), including cytotoxicity [105]. Sepp1 may have a direct role in overall response against oxidative stress [106]. Studies indicate Sepp1 may also reduce aggregation of amyloid beta by chelating zinc and copper, which promote amyloid fibril formation [41, 107].

In another study of postmortem AD brains, Trx protein levels decrease but TrxR activity increased [33]. The increase in TrxR activity may be a compensatory mechanism to the increased oxidative stress. Several studies have suggested a role for SelM in AD [41-43, 108-110]. Deletion of SelM did not result in memory impairments at 3–5 months of age, although by 5–8 months male SelM KO mice had greatly increased insulin levels indicating propensity to diabetes, which is a risk factor for AD [111, 112].

Parkinson's Disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Alzheimer's Disease
  5. Parkinson's Disease
  6. Huntington's Disease
  7. Epilepsy
  8. Concluding Remarks
  9. Acknowledgements
  10. REFERENCES

Pathophysiology of Parkinson's Disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of motor control [113]. PD is marked by a dramatic loss of dopamine (DA) neurons in the midbrain substantia nigra (SN) [114]. Lewy bodies are intracellular inclusion bodies of insoluble protein, particularly alpha-synuclein (AS), formed in these neurons prior to cell loss [115]. Most cases of PD are sporadic caused by unknown environmental and/or genetic factors, or more likely a combination of the two, although familial mutations causative of PD have been identified [116]. Although the origins of PD are not well understood, there are still many factors that contribute to PD, particularly those that increase neurodegeneration of the SN. These factors include mitochondrial malfunction and adenosine triphosphate (ATP) depletion, problems in neurotrophic factors, increase in ROS that may cause oxidative stress, excitotoxicity from excess glutamatergic transmission, and larger than normal quantities of iron associated with neuromelanin (NM) [117]. Lewy body formation and neurodegeneration are possibly due to incorrect processing of proteins, abnormal function of the ubiquitination system, and UPR [118]. Neurodegeneration of the DA system results in slowed movement (bradykinesia). DA neurons are highly sensitive to oxidative stress [119], possibly because of the propensity of DA for auto-oxidation. Loss of DA neurons is an ongoing process that happens before the symptoms occurs and continues as the disease progresses [120].

Selenium and Selenoprotein in Relation to Parkinson's Disease

Selenium may have an important role in PD by alleviating oxidative stress via selenoproteins [80]. Plasma selenium levels decrease in subjects with PD [72]. This may be due to greater selenium utilization for selenoprotein production in the brain, possibly for preventing further oxidative damage. Although Sepp1 is decreased in the SN of postmortem PD brain, accounting for cell loss reveals that Sepp1 is increased relative to the density of surviving SN neurons [48]. Sepp1 also colocalizes with presynaptic terminals in the striatum. Glutathione levels in the midbrain decrease prior to clinical symptoms of the disease [49, 50], impairing GPx function and promoting increased oxidation. As with Sepp1, GPx4 is also decreased in PD SN, but increased relative to cell density [24]. GPx4 colocalizes with the pigment NM in DA neurons, and may promote generation of NM in the absence of glutathione. DJ-1, which is associated with a recessive form of PD, regulates translation of GPx4 [27], and oxidation of DJ-1 increases GPx4 synthesis [25]. Oxidation of dopamine to dopamine quinone, conversely, decreases GPx4 following modification with quinone residues [121]. This could also explain the decrease in GPx1 and GPx4 by methamphetamine in a dopaminergic cell model [122]. Rotenone, an inhibitor of complex I of the electron transport chain (ETC) in neuronal mitochondria that is used to model PD, decreases GPx1 expression mRNA expression and total glutathione in HT22 neuronal cells [26].

Huntington's Disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Alzheimer's Disease
  5. Parkinson's Disease
  6. Huntington's Disease
  7. Epilepsy
  8. Concluding Remarks
  9. Acknowledgements
  10. REFERENCES

Pathophysiology of Huntington's Disease

Huntington's disease (HD) is an autosomal dominant disorder caused by an expansion of CAG repeats of the HAP1 gene on the fourth chromosome [123]. The gene normally encodes for the protein huntingtin, but the mutation results in excess polyglutamines being produced at the amino terminal end of the protein. The onset of the disease is defined by an excess of least 39–42 CAG repeats [123-125]. Because of these excess of repeats, this causes a polyglutamine expansion of the huntingtin protein, which then aggregations into intracellular inclusion bodies preceding neuronal death [124, 126]. Neurodegeneration occurs primarily in the striatum, with loss of medium spiny neurons (MSN) in the basal ganglia [123]. The early stages of HD are characterized primarily by the loss of striatal neurons and astrocytes [124]. In the later stages of the disease, pathology may spread through the globus pallidus, thalamus, hypothalamus, subthalamic nucleus, substantia nigra, and cerebellum [123, 124]. The surviving neuronal cells of HD are characterized by loss of dendrites, dendritic spines, and synaptic connections [124]. In the early stages of the disease, the pathology primarily affects the indirect pathway of the basal ganglia, which is inhibitory and involves dopamine D2-type receptors that extend to the globus pallidus externa (GPe) [123]. The decreased synaptic inhibition results in impaired control of movement, particularly the abrupt involuntary movements that characterize Huntington's chorea. In the later stages of the disease, MSNs of the excitatory direct pathway that connects to the globus pallidus internal segment (GPi) are also lost, resulting in symptoms such as akinesia and dystonia.

Selenium and Selenoproteins in Relation to Huntington's Disease

The oxidative stress in HD is countered by an increase in GPxs [29]. GPx activity in the brain was significantly increased in HD, especially GPx1 in striatum and cerebral cortex and GPx6 in striatum. GPx activity also increased in a rat model of HD using quinolinic acid to induce neurodegeneration [30]. Selenium supplementation reduced oxidative stress and lipid peroxidation in this model. In addition, supplementation with bis-selenide prevented loss of motor function, decreased body weight, and metabolic impairments induced with a 3-nitropropionic acid model of HD [127].

Epilepsy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Alzheimer's Disease
  5. Parkinson's Disease
  6. Huntington's Disease
  7. Epilepsy
  8. Concluding Remarks
  9. Acknowledgements
  10. REFERENCES

Pathology of Epilepsy

Epilepsy is defined by periodic episodes of abnormal electrical activity (seizures) that result in temporary disruption of normal brain function. The types of seizures vary, but may be broadly categorized into partial epilepsy syndromes that have a specific location, or generalized epilepsy syndromes that spread throughout the brain [128]. In generalized epilepsy syndromes, seizures typically originate in both cerebral hemispheres simultaneously. In partial epilepsies, seizures originate in one or more foci, but can spread throughout the brain. Epilepsies can also be classified by etiology as either idiopathic epilepsies or symptomatic epilepsies [129]. Idiopathic epilepsies develop from reappearing unprovoked seizures with unknown cause and absence of apparent neurological problems, and may be influenced by genetic factors. Symptomatic epilepsies are sporadic and characterized by multiple seizures, and have many causes that include cellular and anatomical brain damage, unusual metabolic processes, and inborn brain abnormalities.

Selenium and Selenoprotein in Relation to Epilepsy

Various studies have demonstrated an inverse correlation between serum selenium levels and epileptic seizures [130, 131]. Febrile seizures, which are not abnormal or harmful in childhood development, but if frequent may promote epilepsy, correlate inversely with serum selenium levels [132]. This suggests selenium could have a preventative role against certain types of epilepsy. Selenium deficiency increases risk of seizures in childhood epilepsy [130, 133, 134]. Although selenium deficiency due to malnutrition may be a risk factor for epilepsy [134], a recent study demonstrated decreased serum selenium and zinc levels in subjects with idiopathic intractable epilepsy that were independent of nutrition [135]. Therefore epilepsy may increase utilization of selenium, even under adequate selenium intake, possibly for antioxidant GPx and other proteins that may be necessary to prevent excitotoxicity from seizures. This hypothesis is supported by increases in selenoproteins SelW, GPx1, and TrxR1 observed in excised brain tissue from subjects with severe epilepsy requiring surgery [28]. Selenium supplementation decreased seizures, which returned after discontinuation of supplementation [136].

In animal models of epilepsy, selenium deficiency promotes seizures, while selenium supplementation can decrease seizures [137-139]. Knockout of selenium transport protein Sepp1 increases seizure activity under low selenium conditions, while brain-specific knockout of all selenoproteins results in severe seizures [140]. Brain-specific GPx4 knockout mice are also prone to seizures starting around postnatal day 12 [141]. Selenium supplementation can reduce seizures in animal models of epilepsy [137-139]. Sodium selenite and seleno-DL-methionine can prevent pentylenetetrazole-induced epileptic seizures in mouse models, possibly though a prostaglandin E1 receptor associated mechanism [139]. Thus selenium supplementation may be an important therapy for patients with epilepsy, and adequate dietary selenium.

Concluding Remarks

  1. Top of page
  2. Abstract
  3. Introduction
  4. Alzheimer's Disease
  5. Parkinson's Disease
  6. Huntington's Disease
  7. Epilepsy
  8. Concluding Remarks
  9. Acknowledgements
  10. REFERENCES

Selenium and selenoproteins have the potential to reduce the progression of pathology in several neurodegenerative disorders. Selenium may be important to deter oxidative stress and other detrimental factors in Alzheimer's, Huntington's, and Parkinson's. Research on Alzheimer's disease suggests that selenium and selenoproteins may be potentially helpful in reducing their pathology. However, the mechanistic action is not well understood and requires further investigation. Huntington's disease studies show that GPx activity plays a large role in the circumvention of the disease. The levels of GPx1 and 6 were increased in the striatum of HD subjects, possibly due to the higher amount of oxidative stress associated with striatal DA terminals in HD. Further research into the mechanism would be helpful in understanding this phenomenon. Studies of PD have given an interesting insight as to how selenoprotein production is controlled under oxidative stress. Translational mechanisms facilitate the upregulation of selenoproteins such as GPx4. Further investigations are warranted to determine how regulation of selenoprotein production can assist in combating PD and the other neurodegenerative diseases. Epilepsy research has indicated progress in selenium supplementation against the disease, while adequate selenium levels may further help prevent seizures from developing. However, the role of selenoproteins in epilepsy is not well understood. This knowledge may be helpful in preventing epilepsy and managing the disorder.

Although research suggests the beneficial properties of selenium and protective actions of selenoproteins, more knowledge is needed to understand their roles for developing therapeutic applications. There may be a limit to selenium uptake in neurons and synthesis of selenoproteins. Additionally, high levels of selenium are toxic to neurons [103, 142]. Studies are needed to circumvent the toxic effects of selenium for developing therapies using selenium. Selenate has a lower toxicity than other forms of selenium, and may be a preferable form of supplementation [103, 142]. Additionally, selenomethylselenocysteine (SeMeSeCys) has high utility and low toxicity for promotion of selenoprotein synthesis [143]. The recently discovered compound selenoneine may also be an effective source of selenium [144]. Methods for transporting selenium to specific regions and cells and regulating expression of specific selenoproteins may also facilitate treatments. Overall, research in selenoproteins has great potential for producing important therapeutical approaches for brain disorders.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Alzheimer's Disease
  5. Parkinson's Disease
  6. Huntington's Disease
  7. Epilepsy
  8. Concluding Remarks
  9. Acknowledgements
  10. REFERENCES

The authors thank Elizabeth Nguyen-Wu, Arlene Parubrub, and Stephanie Barayuga for helpful suggestions. This work was supported by NIH GM103466.

REFERENCES

  1. Top of page
  2. Abstract
  3. Introduction
  4. Alzheimer's Disease
  5. Parkinson's Disease
  6. Huntington's Disease
  7. Epilepsy
  8. Concluding Remarks
  9. Acknowledgements
  10. REFERENCES
  • 1
    Bellinger, F. P., Raman, A. V., Reeves, M. A., and Berry, M. J. (2009) Regulation and function of selenoproteins in human disease. Biochem. J. 422, 1122.
  • 2
    Hatfield, D. L., Tsuji, P. A., Carlson, B. A., and Gladyshev, V. N. (2014) Selenium and selenocysteine: roles in cancer, health, and development. Trends Biochem. Sci. 39, 112120.
  • 3
    Reeves, M. A., Bellinger, F. P., and Berry, M. J. (2010) The neuroprotective functions of selenoprotein M and its role in cytosolic calcium regulation. Antioxid. Redox Signal. 12, 809818.
  • 4
    Kieliszek, M. and Blazejak, S. (2013) Selenium: significance, and outlook for supplementation. Nutrition 29, 713718.
  • 5
    Rayman, M. P., Infante, H. G., and Sargent, M. (2008) Food-chain selenium and human health: spotlight on speciation. Br. J. Nutr. 100, 238253.
  • 6
    Schomburg, L., Schweizer, U., and Kohrle, J. (2004) Selenium and selenoproteins in mammals: extraordinary, essential, enigmatic. Cell Mol. Life Sci. 61, 19881995.
  • 7
    Navarro-Alarcon, M. and Cabrera-Vique, C. (2008) Selenium in food and the human body: a review. Sci. Total Environ. 400, 115141.
  • 8
    Rayman, M. P. (2008) Food-chain selenium and human health: emphasis on intake. Br. J. Nutr. 100, 254268.
  • 9
    Rayman, M. P. (2004) The use of high-selenium yeast to raise selenium status: how does it measure up? Br. J. Nutr. 92, 557573.
  • 10
    Dietary Reference Intakes for vitamin C, vitamin E, selenium, and carotenoids: a report of the Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. Washington, DC: National Academy Press, 2000. Reference Intakes, Food and Nutrition Board, Institute of Medicine.
  • 11
    Rayman, M. P. (2012) Selenium and human health. Lancet 379, 12561268.
  • 12
    Hargreaves, M. K., Liu, J., Buchowski, M. S., Patel, K. A., Larson, C. O., et al. (2014) Plasma selenium biomarkers in low income black and white Americans from the southeastern United States. PLoS One 9, e84972.
  • 13
    Berry, M. J., Banu, L., Harney, J. W., and Larsen, P. R. (1993) Functional characterization of the eukaryotic SECIS elements which direct selenocysteine insertion at UGA codons. EMBO J. 12, 33153322.
  • 14
    Small-Howard, A., Morozova, N., Stoytcheva, Z., Forry, E. P., Mansell, J. B., et al. (2006) Supramolecular complexes mediate selenocysteine incorporation in vivo. Mol. Cell. Biol. 26, 23372346.
  • 15
    Howard, M. T., Aggarwal, G., Anderson, C. B., Khatri, S., Flanigan, K. M., et al. (2005) Recoding elements located adjacent to a subset of eukaryal selenocysteine-specifying UGA codons. EMBO J. 24, 15961607.
  • 16
    Kryukov, G. V., Castellano, S., Novoselov, S. V., Lobanov, A. V., Zehtab, O., et al. (2003) Characterization of mammalian selenoproteomes. Science 300, 14391443.
  • 17
    Prast-Nielsen, S., Huang, H. H., and Williams, D. L. (2011) Thioredoxin glutathione reductase: its role in redox biology and potential as a target for drugs against neglected diseases. Biochim. Biophys. Acta 1810, 12621271.
  • 18
    Tamura, T. and Stadtman, T. C. (2002) Mammalian thioredoxin reductases. Methods Enzymol. 347, 297306.
  • 19
    Arner, E. S. and Holmgren, A. (2000) Physiological functions of thioredoxin and thioredoxin reductase [In Process Citation]. Eur. J. Biochem. 267, 61026109.
  • 20
    Selenius, M., Rundlof, A. K., Olm, E., Fernandes, A. P., and Bjornstedt, M. (2010) Selenium and the selenoprotein thioredoxin reductase in the prevention, treatment and diagnostics of cancer. Antioxid. Redox Signal. 12, 867880.
  • 21
    Zhang, S., Rocourt, C., and Cheng, W. H. (2010) Selenoproteins and the aging brain. Mech. Ageing Dev. 131, 253260.
  • 22
    Ansari, M. A., Joshi, G., Huang, Q., Opii, W. O., Abdul, H. M., et al. (2006) In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: relevance to Alzheimer's disease and other oxidative stress-related neurodegenerative disorders. Free Radic. Biol. Med. 41, 16941703.
  • 23
    Chen, L., Na, R., Gu, M., Richardson, A., and Ran, Q. (2008) Lipid peroxidation up-regulates BACE1 expression in vivo: a possible early event of amyloidogenesis in Alzheimer's disease. J. Neurochem. 107, 197207.
  • 24
    Bellinger, F. P., Bellinger, M. T., Seale, L. A., Takemoto, A. S., Raman, A. V., et al. (2011) Glutathione peroxidase 4 is associated with neuromelanin in substantia nigra and dystrophic axons in putamen of Parkinson's brain. Mol. Neurodegener. 6, 8.
  • 25
    Blackinton, J., Kumaran, R., van der Brug, M. P., Ahmad, R., Olson, L., et al. (2009) Post-transcriptional regulation of mRNA associated with DJ-1 in sporadic Parkinson disease. Neurosci. Lett. 452, 811.
  • 26
    Panee, J., Liu, W., Nakamura, K., and Berry, M. J. (2007) The responses of HT22 cells to the blockade of mitochondrial complexes and potential protective effect of selenium supplementation. Int. J. Biol. Sci. 3, 335341.
  • 27
    van der Brug, M. P., Blackinton, J., Chandran, J., Hao, L. Y., Lal, A., et al. (2008) RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways. Proc. Natl. Acad. Sci. USA 105, 1024410249.
  • 28
    Yuzbasioglu, A., Karatas, H., Gursoy-Ozdemir, Y., Saygi, S., Akalan, N., et al. (2009) Changes in the expression of selenoproteins in mesial temporal lobe epilepsy patients. Cell Mol. Neurobiol. 29, 12231231.
  • 29
    Sorolla, M. A., Reverter-Branchat, G., Tamarit, J., Ferrer, I., Ros, J., et al. (2008) Proteomic and oxidative stress analysis in human brain samples of Huntington disease. Free Radic. Biol. Med. 45, 667678.
  • 30
    Sreekala, S. and Indira, M. (2009) Impact of co administration of selenium and quinolinic acid in the rat's brain. Brain Res. 1281, 101107.
  • 31
    Ursini, F., Maiorino, M., and Gregolin, C. (1985) The selenoenzyme phospholipid hydroperoxide glutathione peroxidase. Biochim. Biophys. Acta 839, 6270.
  • 32
    Schweizer, U., Brauer, A. U., Kohrle, J., Nitsch, R., and Savaskan, N. E. (2004) Selenium and brain function: a poorly recognized liaison. Brain Res. Brain Res. Rev. 45, 164178.
  • 33
    Lovell, M. A., Xie, C., Gabbita, S. P., and Markesbery, W. R. (2000) Decreased thioredoxin and increased thioredoxin reductase levels in Alzheimer's disease brain. Free Radic. Biol. Med. 28, 418427.
  • 34
    Bates, J. M., St. Germain, D. L., and Galton, V. A. (1999) Expression profiles of the three iodothyronine deiodinases, D1, D2, and D3, in the developing rat. Endocrinology 140, 844851.
  • 35
    Novoselov, S. V., Kryukov, G. V., Xu, X. M., Carlson, B. A., Hatfield, D. L., et al. (2007) Selenoprotein H is a nucleolar thioredoxin-like protein with a unique expression pattern. J. Biol. Chem. 282, 1196011968.
  • 36
    Panee, J., Stoytcheva, Z. R., Liu, W., and Berry, M. J. (2007) Selenoprotein H is a redox-sensing HMG family DNA-binding protein that upregulates genes involved in glutathione synthesis and phase II detoxification. J. Biol. Chem. 282, 2375923765.
  • 37
    Shchedrina, V. A., Everley, R. A., Zhang, Y., Gygi, S. P., Hatfield, D. L., et al. (2011) Selenoprotein K binds multiprotein complexes and is involved in the regulation of endoplasmic reticulum homeostasis. J. Biol. Chem. 286, 4293742948.
  • 38
    Meiler, S., Baumer, Y., Huang, Z., Hoffmann, F. W., Fredericks, G. J., et al. (2013) Selenoprotein K is required for palmitoylation of CD36 in macrophages: implications in foam cell formation and atherogenesis. J. Leukoc. Biol. 93, 771780.
  • 39
    Huang, Z., Hoffmann, F. W., Fay, J. D., Hashimoto, A. C., Chapagain, M. L., et al. (2012) Stimulation of unprimed macrophages with immune complexes triggers a low output of nitric oxide by calcium-dependent neuronal nitric-oxide synthase. J. Biol. Chem. 287, 44924502.
  • 40
    Yim, S. Y., Chae, K. R., Shim, S. B., Hong, J. T., Park, J. Y., et al. (2009) ERK activation induced by selenium treatment significantly downregulates beta/gamma-secretase activity and Tau phosphorylation in the transgenic rat overexpressing human selenoprotein M. Int. J. Mol. Med. 24, 9196.
  • 41
    Du, X., Li, H., Wang, Z., Qiu, S., Liu, Q., et al. (2013) Selenoprotein P and selenoprotein M block Zn2+ -mediated Abeta42 aggregation and toxicity. Metallomics 5, 861870.
  • 42
    Chen, P., Wang, R. R., Ma, X. J., Liu, Q., and Ni, J. Z. (2013) Different forms of selenoprotein M differentially affect abeta aggregation and ROS generation. Int. J. Mol. Sci. 14, 43854399.
  • 43
    Hwang, D. Y., Cho, J. S., Oh, J. H., Shim, S. B., Jee, S. W., et al. (2005) Differentially expressed genes in transgenic mice carrying human mutant presenilin-2 (N141I): correlation of selenoprotein M with Alzheimer's disease. Neurochem. Res. 30, 10091019.
  • 44
    Nakayama, A., Hill, K. E., Austin, L. M., Motley, A. K., and Burk, R. F. (2007) All regions of mouse brain are dependent on selenoprotein P for maintenance of selenium. J. Nutr. 137, 690693.
  • 45
    Bellinger, F. P., He, Q. P., Bellinger, M. T., Lin, Y., Raman, A. V., et al. (2008) Association of selenoprotein p with Alzheimer's pathology in human cortex. J. Alzheimers Dis. 15, 465472.
  • 46
    Peters, M. M., Hill, K. E., Burk, R. F., and Weeber, E. J. (2006) Altered hippocampus synaptic function in selenoprotein P deficient mice. Mol. Neurodegener. 1, 12.
  • 47
    Takemoto, A. S., Berry, M. J., and Bellinger, F. P. (2010) Role of selenoprotein P in Alzheimer's disease. Ethn. Dis. 20, S192.
  • 48
    Bellinger, F. P., Raman, A. V., Rueli, R. H., Bellinger, M. T., Dewing, A. S., et al. (2012) Changes in Selenoprotein P in substantia nigra and Putamen in Parkinson's disease. J. Parkinsons. Dis. 2, 115126.
  • 49
    Perry, T. L., Godin, D. V., and Hansen, S. (1982) Parkinson's disease: a disorder due to nigral glutathione deficiency? Neurosci. Lett. 33, 305310.
  • 50
    Perry, T. L. and Yong, V. W. (1986) Idiopathic Parkinson's disease, progressive supranuclear palsy and glutathione metabolism in the substantia nigra of patients. Neurosci. Lett. 67, 269274.
  • 51
    Fradejas, N., Pastor, M. D., Mora-Lee, S., Tranque, P., and Calvo, S. (2008) SEPS1 gene is activated during astrocyte ischemia and shows prominent antiapoptotic effects. J. Mol. Neurosci. 35, 259265.
  • 52
    Grumolato, L., Ghzili, H., Montero-Hadjadje, M., Gasman, S., Lesage, J., et al. (2008) Selenoprotein T is a PACAP-regulated gene involved in intracellular Ca2+ mobilization and neuroendocrine secretion. FASEB J. 22, 17561768.
  • 53
    Stefaniuk, M. and Lukasiuk, K. (2010) Cloning of expressed sequence tags (ESTs) representing putative epileptogenesis-related genes and the localization of their expression in the normal brain. Neurosci. Lett. 482, 230234.
  • 54
    Raman, A. V., Pitts, M. W., Seyedali, A., Hashimoto, A. C., Bellinger, F. P., et al. (2013) Selenoprotein W expression and regulation in mouse brain and neurons. Brain Behav. 3, 562574.
  • 55
    Lee, B. C., Peterfi, Z., Hoffmann, F. W., Moore, R. E., Kaya, A., et al. (2013) MsrB1 and MICALs regulate actin assembly and macrophage function via reversible stereoselective methionine oxidation. Mol. Cell 51, 397404.
  • 56
    Moskovitz, J., Maiti, P., Lopes, D. H., Oien, D. B., Attar, A., et al. (2011) Induction of methionine-sulfoxide reductases protects neurons from amyloid beta-protein insults in vitro and in vivo. Biochemistry 50, 1068710697.
  • 57
    Lu, J. and Holmgren, A. (2009) Selenoproteins. J. Biol. Chem. 284, 723727.
  • 58
    Holben, D. H. and Smith, A. M. (1999) The diverse role of selenium within selenoproteins: a review. J. Am. Diet Assoc. 99, 836843.
  • 59
    Ursini, F., Heim, S., Kiess, M., Maiorino, M., Roveri, A., et al. (1999) Dual function of the selenoprotein PHGPx during sperm maturation. Science 285, 13931396.
  • 60
    Larsen, P. R. and Berry, M. J. (1995) Nutritional and hormonal regulation of thyroid hormone deiodinases. Annu. Rev. Nutr. 15, 323352.
  • 61
    Beckett, G. J. and Arthur, J. R. (2005) Selenium and endocrine systems. J. Endocrinol. 184, 455465.
  • 62
    St. Germain, D. L. and Galton, V. A. (1997) The deiodinase family of selenoproteins. Thyroid 7, 655668.
  • 63
    Burk, R. F. and Hill, K. E. (2009) Selenoprotein P-expression, functions, and roles in mammals. Biochim. Biophys. Acta 1790, 14411447.
  • 64
    Shchedrina, V. A., Zhang, Y., Labunskyy, V. M., Hatfield, D. L., and Gladyshev, V. N. (2010) Structure-function relations, physiological roles, and evolution of mammalian ER-resident selenoproteins. Antioxid. Redox Signal. 12, 839849.
  • 65
    Xia, L., Nordman, T., Olsson, J. M., Damdimopoulos, A., Bjorkhem-Bergman, L., et al. (2003) The mammalian cytosolic selenoenzyme thioredoxin reductase reduces ubiquinone. A novel mechanism for defense against oxidative stress. J. Biol. Chem. 278, 21412146.
  • 66
    Labunskyy, V. M., Yoo, M. H., Hatfield, D. L., and Gladyshev, V. N. (2009) Sep15, a thioredoxin-like selenoprotein, is involved in the unfolded protein response and differentially regulated by adaptive and acute ER stresses. Biochemistry 48, 84588465.
  • 67
    Horibata, Y. and Hirabayashi, Y. (2007) Identification and characterization of human ethanolaminephosphotransferase1. J. Lipid Res. 48, 503508.
  • 68
    Novoselov, S. V., Kim, H. Y., Hua, D., Lee, B. C., Astle, C. M., et al. (2010) Regulation of selenoproteins and methionine sulfoxide reductases A and B1 by age, calorie restriction, and dietary selenium in mice. Antioxid. Redox Signal. 12, 829838.
  • 69
    Akbaraly, T. N., Hininger-Favier, I., Carriere, I., Arnaud, J., Gourlet, V., et al. (2007) Plasma selenium over time and cognitive decline in the elderly. Epidemiology 18, 5258.
  • 70
    Berr, C., Balansard, B., Arnaud, J., Roussel, A. M., and Alperovitch, A. (2000) Cognitive decline is associated with systemic oxidative stress: the EVA study. Etude du Vieillissement Arteriel. J. Am. Geriatr. Soc. 48, 12851291.
  • 71
    Gao, S., Jin, Y., Hall, K. S., Liang, C., Unverzagt, F. W., et al. (2007) Selenium level and cognitive function in rural elderly Chinese. Am. J. Epidemiol. 165, 955965.
  • 72
    Shahar, A., Patel, K. V., Semba, R. D., Bandinelli, S., Shahar, D. R., et al. (2010) Plasma selenium is positively related to performance in neurological tasks assessing coordination and motor speed. Mov. Disord. 25, 19091915.
  • 73
    Agamy, O., Ben Zeev, B., Lev, D., Marcus, B., Fine, D., et al. (2010) Mutations disrupting selenocysteine formation cause progressive cerebello-cerebral atrophy. Am. J. Hum. Genet. 87, 538544.
  • 74
    Ben-Zeev, B., Hoffman, C., Lev, D., Watemberg, N., Malinger, G., et al. (2003) Progressive cerebellocerebral atrophy: a new syndrome with microcephaly, mental retardation, and spastic quadriplegia. J. Med. Genet. 40, e96.
  • 75
    Palioura, S., Sherrer, R. L., Steitz, T. A., Soll, D., and Simonovic, M. (2009) The human SepSecS-tRNASec complex reveals the mechanism of selenocysteine formation. Science 325, 321325.
  • 76
    Prohaska, J. R. and Ganther, H. E. (1976) Selenium and glutathione peroxidase in developing rat brain. J. Neurochem. 27, 13791387.
  • 77
    Kyriakopoulos, A., Rothlein, D., Pfeifer, H., Bertelsmann, H., Kappler, S., et al. (2000) Detection of small selenium-containing proteins in tissues of the rat. J. Trace Elem. Med. Biol. 14, 179183.
  • 78
    Ursini, F. and Bindoli, A. (1987) The role of selenium peroxidases in the protection against oxidative damage of membranes. Chem. Phys. Lipids 44, 255276.
  • 79
    Sun, Y., Gu, Q. P., and Whanger, P. D. (2001) Selenoprotein W in overexpressed and underexpressed rat glial cells in culture. J. Inorg. Biochem. 84, 151156.
  • 80
    Chen, J. and Berry, M. J. (2003) Selenium and selenoproteins in the brain and brain diseases. J. Neurochem. 86, 112.
  • 81
    Ellison, D., Love, S., Chimelli, L., Harding, B. N., Lowe, J. S., Vinters, H. V., Brandner, S., Yong, W.H. (2013) Neuropathology: a reference text of CNS pathology. pp. 567628. Mosby, Edinburgh.
  • 82
    Small, S.A., Mayeux, R. (2010). Alzheimer disease. In Merritt's Neurology, 12th ed. (Rowland, L.P. and Pedley, T.A. eds.) pp. 713 – 718. Lippincott Williams and Wilkins, Philadelphia.
  • 83
    Fahn, S. and Przedborski, S. (2010) Parkinson disease. In Merritt's Neurology (Rowland, L.P. and Pedley, T.A., eds.). pp. 751769. Lippincott Williams and Wilkins, Philadelphia.
  • 84
    Fahn, S. and Jankovic. J. (2010) Huntington disease. In Merritt's Neurology, 12th ed. (Rowland, L.P. and Pedley, T.A., eds.). pp. 723726. Lippincott Williams and Wilkins, Philadelphia.
  • 85
    Bazil, C. W. and Pedley, T. A. (2010) Epilepsy. In Merritt's Neurology, 12th ed. (Rowland, L.P. and Pedley, T.A., eds.). pp. 927948. Lippincott Williams and Wilkins, Philadelphia.
  • 86
    Miller, D. C. (2009) Modern surgical neuropathology. pp. 467506. Cambridge University Press, Cambridge.
  • 87
    Barral, S., Bird, T., Goate, A., Farlow, M. R., Diaz-Arrastia, R., et al. (2012) Genotype patterns at PICALM, CR1, BIN1, CLU, and APOE genes are associated with episodic memory. Neurology 78, 14641471.
  • 88
    Govert, F. and Schneider, S. A. (2013) Huntington's disease and Huntington's disease-like syndromes: an overview. Curr. Opin. Neurol. 26, 420427.
  • 89
    Helbig, I. and Lowenstein, D. H. (2013) Genetics of the epilepsies: where are we and where are we going? Curr. Opin. Neurol. 26, 179185.
  • 90
    Lesage, S. and Brice, A. (2009) Parkinson's disease: from monogenic forms to genetic susceptibility factors. Hum. Mol. Genet. 18, R48R59.
  • 91
    Bellinger, F. P. and Weeber, E. J. (2012) Selenium in Alzheimer's disease. In Selenium—Its Molecular Biology and Role in Human Health (Hatfield, D. L., Berry, M. J., and Gladyshev, V.N., eds.). pp. 433442, Springer, New York.
  • 92
    Chouliaras, L., Sierksma, A. S., Kenis, G., Prickaerts, J., Lemmens, M. A., et al. (2010) Gene-environment interaction research and transgenic mouse models of Alzheimer's disease. Int. J. Alzheimers Dis. 2010.
  • 93
    Huse, J. T. and Doms, R.W. (2001) Neurotoxic traffic: uncovering the mechanics of amyloid production in Alzheimer's disease. Traffic 2, 7581.
  • 94
    Butterfield, D. A., Perluigi, M., and Sultana, R. (2006) Oxidative stress in Alzheimer's disease brain: new insights from redox proteomics. Eur. J. Pharmacol. 545, 3950.
  • 95
    Spires-Jones, T. L., Stoothoff, W. H., de Calignon, A., Jones, P. B., and Hyman, B. T. (2009) Tau pathophysiology in neurodegeneration: a tangled issue. Trends Neurosci. 32, 150159.
  • 96
    Vural, H., Demirin, H., Kara, Y., Eren, I., and Delibas, N. (2010) Alterations of plasma magnesium, copper, zinc, iron and selenium concentrations and some related erythrocyte antioxidant enzyme activities in patients with Alzheimer's disease. J. Trace Elem. Med. Biol. 24, 169173.
  • 97
    Cardoso, B. R., Ong, T. P., Jacob-Filho, W., Jaluul, O., Freitas, M. I., et al. (2010) Nutritional status of selenium in Alzheimer's disease patients. Br. J. Nutr. 103, 803806.
  • 98
    Xiong, S., Markesbery, W. R., Shao, C., and Lovell, M. A. (2007) Seleno-L-methionine protects against beta-amyloid and iron/hydrogen peroxide-mediated neuron death. Antioxid. Redox Signal. 9, 457467.
  • 99
    Lovell, M. A., Xiong, S., Lyubartseva, G., and Markesbery, W. R. (2009) Organoselenium (Sel-Plex diet) decreases amyloid burden and RNA and DNA oxidative damage in APP/PS1 mice. Free Radic. Biol. Med. 46, 15271533.
  • 100
    Tung, Y. T., Hsu, W. M., Wang, B. J., Wu, S. Y., Yen, C. T., et al. (2008) Sodium selenite inhibits gamma-secretase activity through activation of ERK. Neurosci. Lett. 440, 3843.
  • 101
    Ishrat, T., Parveen, K., Khan, M. M., Khuwaja, G., Khan, M. B., et al. (2009) Selenium prevents cognitive decline and oxidative damage in rat model of streptozotocin-induced experimental dementia of Alzheimer's type. Brain Res. 1281, 117127.
  • 102
    Haratake, M., Yoshida, S., Mandai, M., Fuchigami, T., and Nakayama, M. (2013) Elevated amyloid-beta plaque deposition in dietary selenium-deficient Tg2576 transgenic mice. Metallomics 5, 479483.
  • 103
    Corcoran, N. M., Martin, D., Hutter-Paier, B., Windisch, M., Nguyen, T., et al. (2010) Sodium selenate specifically activates PP2A phosphatase, dephosphorylates tau and reverses memory deficits in an Alzheimer's disease model. J. Clin. Neurosci. 17, 10251033.
  • 104
    van Eersel, J., Ke, Y. D., Liu, X., Delerue, F., Kril, J. J., et al. (2010) Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models. Proc. Natl. Acad. Sci. USA 107, 1388813893.
  • 105
    Steinbrenner, H., Alili, L., Bilgic, E., Sies, H., and Brenneisen, P. (2006) Involvement of selenoprotein P in protection of human astrocytes from oxidative damage. Free Radic. Biol. Med. 40, 15131523.
  • 106
    Arteel, G. E., Mostert, V., Oubrahim, H., Briviba, K., Abel, J., et al. (1998) Protection by selenoprotein P in human plasma against peroxynitrite-mediated oxidation and nitration. Biol. Chem. 379, 12011205.
  • 107
    Du, X., Wang, Z., Zheng, Y., Li, H., Ni, J., et al. (2014) Inhibitory effect of selenoprotein P on Cu/Cu-induced abeta aggregation and toxicity. Inorg Chem. 53, 16721678.
  • 108
    Hwang, D. Y., Sin, J. S., Kim, M. S., Yim, S. Y., Kim, Y. K., et al. (2008) Overexpression of human selenoprotein M differentially regulates the concentrations of antioxidants and H2O2, the activity of antioxidant enzymes, and the composition of white blood cells in a transgenic rat. Int. J. Mol. Med. 21, 169179.
  • 109
    Korotkov, K. V., Novoselov, S. V., Hatfield, D. L., and Gladyshev, V. N. (2002) Mammalian selenoprotein in which selenocysteine (Sec) incorporation is supported by a new form of Sec insertion sequence element. Mol. Cell. Biol. 22, 14021411.
  • 110
    Qiao, X., Tian, J., Chen, P., Wang, C., Ni, J., et al. (2013) Galectin-1 is an interactive protein of selenoprotein M in the brain. Int. J. Mol. Sci. 14, 2223322245.
  • 111
    Manolopoulos, K. N., Klotz, L. O., Korsten, P., Bornstein, S. R., and Barthel, A. (2010) Linking Alzheimer's disease to insulin resistance: the FoxO response to oxidative stress. Mol. Psychiatry 15, 10461052.
  • 112
    Pitts, M. W., Reeves, M. A., Hashimoto, A. C., Ogawa, A., Kremer, P., et al. (2013) Deletion of selenoprotein M leads to obesity without cognitive deficits. J. Biol. Chem. 288, 2612126134.
  • 113
    Fahn, S. (2003) Description of Parkinson's disease as a clinical syndrome. Ann. N. Y. Acad. Sci. 991, 114.
  • 114
    Chinta, S. J. and Andersen, J. K. (2005) Dopaminergic neurons. Int. J. Biochem. Cell Biol. 37, 942946.
  • 115
    Galvin, J. E., Lee, V. M., Schmidt, M. L., Tu, P. H., et al. (1999) Pathobiology of the Lewy body. Adv. Neurol. 80, 313324.
  • 116
    Greenamyre, J. T. and Hastings, T. G. (2004) Biomedicine. Parkinson's—divergent causes, convergent mechanisms. Science 304, 11201122.
  • 117
    Gandhi, S. and Wood, N. W. (2005) Molecular pathogenesis of Parkinson's disease. Hum. Mol. Genet. 14, 27492755.
  • 118
    Alladi, P. A., Mahadevan, A., Vijayalakshmi, K., Muthane, U., Shankar, S. K. et al. (2010) Ageing enhances alpha-synuclein, ubiquitin and endoplasmic reticular stress protein expression in the nigral neurons of Asian Indians. Neurochem. Int. 57, 530539.
  • 119
    Licker, V., Kovari, E., Hochstrasser, D. F., and Burkhard P. R. (2009) Proteomics in human Parkinson's disease research. J. Proteomics 73, 1029.
  • 120
    Thobois, S., Guillouet, S., and Broussolle, E. (2001) Contributions of PET and SPECT to the understanding of the pathophysiology of Parkinson's disease. Neurophysiol. Clin. 31, 321340.
  • 121
    Hauser, D. N., Dukes, A. A., Mortimer, A. D., and Hastings, T. G. (2013) Dopamine quinone modifies and decreases the abundance of the mitochondrial selenoprotein glutathione peroxidase 4. Free Radic. Biol. Med. 65, 419427.
  • 122
    Barayuga, S. M., Pang, X., Andres, M. A., Panee, J., and Bellinger, F. P. (2013) Methamphetamine decreases levels of glutathione peroxidases 1 and 4 in SH-SY5Y neuronal cells: protective effects of selenium. Neurotoxicology 37, 240246.
  • 123
    Raymond, L. A., Andre, V. M., Cepeda, C., Gladding, C. M., Milnerwood, A. J., et al. (2011) Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function. Neuroscience 198, 252273.
  • 124
    Hickey, M. A. and Chesselet, M.-F. (2003) Apoptosis in Huntington's disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 27, 255265.
  • 125
    Levine, M. S., Cepeda, C., Hickey, M. A., Fleming, S. M., and Chesselet, M. F. (2004) Genetic mouse models of Huntington's and Parkinson's diseases: illuminating but imperfect. Trends Neurosci. 27, 691697.
  • 126
    Hoffner, G. and Djian, P. (2002) Protein aggregation in Huntington's disease. Biochimie 84, 273278.
  • 127
    Bortolatto, C. F., Jesse, C. R., Wilhelm, E. A., Chagas, P. M., and Nogueira, C. W. (2013) Organoselenium bis selenide attenuates 3-nitropropionic acid-induced neurotoxicity in rats. Neurotox. Res. 23, 214224.
  • 128
    Chang, B. S. and Lowenstein, D. H. (2003) Epilepsy. N. Engl. J. Med. 349, 12571266.
  • 129
    Elger, C. E. and Schmidt, D. (2008) Modern management of epilepsy: a practical approach. Epilepsy Behav. 12, 501539.
  • 130
    Ashrafi, M. R., Shams, S., Nouri, M., Mohseni, M., Shabanian, R., et al. (2007) A probable causative factor for an old problem: selenium and glutathione peroxidase appear to play important roles in epilepsy pathogenesis. Epilepsia 48, 17501755.
  • 131
    Ashrafi, M. R., Shabanian, R., Abbaskhanian, A., Nasirian, A., Ghofrani, M., et al. (2007) Selenium and intractable epilepsy: is there any correlation? Pediatr. Neurol. 36, 2529.
  • 132
    Mahyar, A., Ayazi, P., Fallahi, M., and Javadi, A. (2010) Correlation between serum selenium level and febrile seizures. Pediatr. Neurol. 43, 331334.
  • 133
    Thiel, R. and Fowkes, S. W. (2007) Down syndrome and thyroid dysfunction: should nutritional support be the first-line treatment? Med. Hypotheses 69, 809815.
  • 134
    Volpe, S. L., Schall, J. I., Gallagher, P. R., Stallings, V. A., and Bergqvist, A. G. (2007) Nutrient intake of children with intractable epilepsy compared with healthy children. J. Am. Diet Assoc. 107, 10141018.
  • 135
    Seven, M., Basaran, S. Y., Cengiz, M., Unal, S., and Yuksel, A. (2013) Deficiency of selenium and zinc as a causative factor for idiopathic intractable epilepsy. Epilepsy Res. 104, 3539.
  • 136
    Ramaekers, V. T., Calomme, M., Vanden Berghe, D., and Makropoulos, W. (1994) Selenium deficiency triggering intractable seizures. Neuropediatrics 25, 217223.
  • 137
    Naziroglu, M., Kutluhan, S., and Yilmaz, M. (2008) Selenium and topiramate modulates brain microsomal oxidative stress values, Ca2+-ATPase activity, and EEG records in pentylentetrazol-induced seizures in rats. J. Membr. Biol. 225, 3949.
  • 138
    Oztas, B., Kilic, S., Dural, E., and Ispir, T. (2001) Influence of antioxidants on the blood-brain barrier permeability during epileptic seizures. J. Neurosci. Res. 66, 674678.
  • 139
    Rehni, A. K. and Singh, T. G. (2012) Selenium induced anticonvulsant effect: a potential role of prostaglandin E(1) receptor activation linked mechanism. J. Trace Elem. Med. Biol. 27, 3139.
  • 140
    Wirth, E. K., Conrad, M., Winterer, J., Wozny, C., Carlson, B. A., et al. (2010) Neuronal selenoprotein expression is required for interneuron development and prevents seizures and neurodegeneration. FASEB J. 24, 844852.
  • 141
    Seiler, A., Schneider, M., Forster, H., Roth, S., Wirth, E. K., et al. (2008) Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab. 8, 237248.
  • 142
    Biswas, S., Talukder, G., and Sharma, A. (1999) Comparison of clastogenic effects of inorganic selenium salts in mice in vivo as related to concentrations and duration of exposure. Biometals 12, 361368.
  • 143
    Hoefig, C. S., Renko, K., Kohrle, J., Birringer, M., and Schomburg, L. (2011) Comparison of different selenocompounds with respect to nutritional value vs. toxicity using liver cells in culture. J. Nutr. Biochem. 22, 945955.
  • 144
    Yamashita, Y. and Yamashita, M. (2010) Identification of a novel selenium-containing compound, selenoneine, as the predominant chemical form of organic selenium in the blood of bluefin tuna. J. Biol. Chem. 285, 1813418138.