Lucia A. Seale

Pacific Biosciences (United States)

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Marla J. Berry

University of Hawaii System

Ann C. Hashimoto

University of Hawaiʻi at Mānoa

Daniel J. Torres

University of Hawaiʻi at Mānoa

Matthew W. Pitts

University of Hawaiʻi at Mānoa

Pamela Toh

Icahn School of Medicine at Mount Sinai

Lígia Moriguchi Watanabe

Universidade de São Paulo

Christy L. Gilman

University of Virginia

Ali Seyedali

University of Hawaiʻi at Mānoa

Sydonie Swanson

University of Hawaiʻi at Mānoa

Ashley N. Ogawa-Wong

Brigham and Women's Hospital

Cooperative Institutions

University of Hawaiʻi at Mānoa

University of Hawaii System

Universidade de São Paulo

Pacific Biosciences (United States)

University of Hawaii Cancer Center

Harvard University

Cancer Center of Hawaii

German Cancer Research Center

Heidelberg University

Brigham and Women's Hospital

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Effects of Selenium Supplementation in Obese Selenocysteine Lyase Knockout Mouse (P24-022-19)

Current Developments in Nutrition (2019)

Lígia Moriguchi Watanabe Ann C. Hashimoto Marla J. Berry Lucia A. Seale

We previously demonstrated that disruption of selenocysteine lyase (Scly) in mice leads to the development of obesity and metabolic syndrome under selenium deficiency, with effects on glucose homeostasis in the liver. It is unknown whether the physiology of skeletal muscle, a key tissue in glucose disposal, is also affected by the disruption of Scly. Here, we investigated the effects of a high-fat diet supplemented with selenium in the muscle physiology of Scly knockout (KO) mice Age-matched homozygous male and female Scly KO and wild type (WT) from C57BL/6 J background were group-caged and fed for three months to a diet containing 45% kcal fat and 0.25 ppm (adequate) or 1 ppm (high) of selenium as sodium selenite. Serum, liver, soleus, and brown adipose tissue (BAT) were collected and assessed for total glutathione peroxidase (GPX) activity and creatine kinase (CK). Total RNA was extracted from soleus and liver, reverse-transcribed, and used in qPCR. Following an adequate selenium intake, total GPX activity in serum, mRNA of GPX1 and selenoprotein P in the liver, and mRNA of selenoprotein N in soleus were unchanged of Scly KO compared to WT mice, both in males and females. We observed five-fold increase of CK activity in serum and a one-fold decrease in soleus of Scly KO male mice when compared with WT. Increased CK levels in serum have been related with muscle impairment. Interestingly, when male Scly KO mice were fed a high selenium diet, we observed the opposite effect, with serum CK activity significantly decreased, while in soleus CK activity increased in Scly KO mice. CK activity levels on liver or BAT were unchanged. CK activity in serum was unchanged in female mice, corroborating to the previously described sexual dimorphism for these animals. These results suggest an improvement in Scly KO muscle health after selenium supplementation. Adequate selenium levels maintain selenium homeostasis and ensure the maintenance of selenoprotein levels, but high selenium intake may be necessary to preserve muscle health. FAPESP/Brazil, NIDDK-NIH/USA, NIMHD-NIH/USA.

Selenoprotein

GPX1

Selenocysteine

Homeostasis

10.1093/cdn/nzz044.p24-022-19

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Citations (0)

Absence of selenoprotein P but not selenocysteine lyase results in severe neurological dysfunction

Genes Brain & Behavior (2012)

Arjun V. Raman Matthew W. Pitts Ali Seyedali A. Hashimoto Lucia A. Seale

Dietary selenium restriction in mammals causes bodily selenium to be preferentially retained in the brain relative to other organs. Almost all the known selenoproteins are found in brain, where expression is facilitated by selenocysteine (Sec)-laden selenoprotein P. The brain also expresses selenocysteine lyase (Scly), an enzyme that putatively salvages Sec and recycles the selenium for selenoprotein translation. We compared mice with a genetic deletion of Scly to selenoprotein P (Sepp1) knockout mice for similarity of neurological impairments and whether dietary selenium modulates these parameters. We report that Scly knockout mice do not display neurological dysfunction comparable to Sepp1 knockout mice. Feeding a low-selenium diet to Scly knockout mice revealed a mild spatial learning deficit without disrupting motor coordination. Additionally, we report that the neurological phenotype caused by the absence of Sepp1 is exacerbated in male vs. female mice. These findings indicate that Sec recycling via Scly becomes limiting under selenium deficiency and suggest the presence of a complementary mechanism for processing Sec. Our studies illuminate the interaction between Sepp1 and Scly in the distribution and turnover of body and brain selenium and emphasize the consideration of sex differences when studying selenium and selenoproteins in vertebrate biology.

Selenocysteine

Selenoprotein

Selenoprotein P

Knockout mouse

Selenium deficiency

10.1111/j.1601-183x.2012.00794.x

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Citations (58)

From Selenium Absorption to Selenoprotein Degradation

Biological Trace Element Research (2019)

Herena Y. Ha Naghum Alfulaij Marla J. Berry Lucia A. Seale

Selenoprotein

Selenoprotein P

Degradation

10.1007/s12011-019-01771-x

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Citations (103)

THE EFFECT OF GLUCOCORTICOIDS ON HIPPOCAMPAL SELENOPROTEINS

IBRO Neuroscience Reports (2023)

Jessica Nicholson Matthew W. Pitts Stella Maris A. Remigio Lucia A. Seale Marla J. Berry

10.1016/j.ibneur.2023.08.1572

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Glutathione Peroxidase 4 is associated with Neuromelanin in Substantia Nigra and Dystrophic Axons in Putamen of Parkinson's brain

Molecular Neurodegeneration (2011)

Frederick P. Bellinger Miyoko T. Bellinger Lucia A. Seale Andrea S. Takemoto Arjun V. Raman

Parkinson's disease is a neurodegenerative disorder characterized pathologically by the loss of nigrostriatal dopamine neurons that project from the substantia nigra in the midbrain to the putamen and caudate nuclei, leading to the clinical features of bradykinesia, rigidity, and rest tremor. Oxidative stress from oxidized dopamine and related compounds may contribute to the degeneration characteristic of this disease.To investigate a possible role of the phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4) in protection from oxidative stress, we investigated GPX4 expression in postmortem human brain tissue from individuals with and without Parkinson's disease. In both control and Parkinson's samples, GPX4 was found in dopaminergic nigral neurons colocalized with neuromelanin. Overall GPX4 was significantly reduced in substantia nigra in Parkinson's vs. control subjects, but was increased relative to the cell density of surviving nigral cells. In putamen, GPX4 was concentrated within dystrophic dopaminergic axons in Parkinson's subjects, although overall levels of GPX4 were not significantly different compared to control putamen.This study demonstrates an up-regulation of GPX4 in neurons of substantia nigra and association of this protein with dystrophic axons in striatum of Parkinson's brain, indicating a possible neuroprotective role. Additionally, our findings suggest this enzyme may contribute to the production of neuromelanin.

Neuromelanin

Putamen

10.1186/1750-1326-6-8

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Citations (140)

Prolonged maternal exposure to glucocorticoids alters selenoprotein expression in the developing brain

Frontiers in Molecular Neuroscience (2023)

Pamela Toh Lucia A. Seale Marla J. Berry Daniel J. Torres

Aberrant activation of the stress-response system in early life can alter neurodevelopment and cause long-term neurological changes. Activation of the hypothalamic–pituitary–adrenal axis releases glucocorticoids into the bloodstream, to help the organism adapt to the stressful stimulus. Elevated glucocorticoid levels can promote the accumulation of reactive oxygen species, and the brain is highly susceptible to oxidative stress. The essential trace element selenium is obtained through diet, is used to synthesize antioxidant selenoproteins, and can mitigate glucocorticoid-mediated oxidative damage. Glucocorticoids can impair antioxidant enzymes in the brain, and could potentially influence selenoprotein expression. We hypothesized that exposure to high levels of glucocorticoids would disrupt selenoprotein expression in the developing brain. C57 wild-type dams of recently birthed litters were fed either a moderate (0.25 ppm) or high (1 ppm) selenium diet and administered corticosterone (75 μg/ml) via drinking water during postnatal days 1 to 15, after which the brains of the offspring were collected for western blot analysis. Glutathione peroxidase 1 and 4 levels were increased by maternal corticosterone exposure within the prefrontal cortex, hippocampus, and hypothalamus of offspring. Additionally, levels of the glucocorticoid receptor were decreased in the hippocampus and selenoprotein W was elevated in the hypothalamus by corticosterone. Maternal consumption of a high selenium diet independently decreased glucocorticoid receptor levels in the hippocampus of offspring of both sexes, as well as in the prefrontal cortex of female offspring. This study demonstrates that early life exposure to excess glucocorticoid levels can alter selenoprotein levels in the developing brain.

Corticosterone

Selenoprotein

10.3389/fnmol.2023.1115993

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Citations (1)

Disruption of the Selenocysteine Lyase-Mediated Selenium Recycling Pathway Leads to Metabolic Syndrome in Mice

Molecular and Cellular Biology (2012)

Lucia A. Seale Ann C. Hashimoto Suguru Kurokawa Christy L. Gilman Ali Seyedali

Selenium (Se) is an essential trace element used for biosynthesis of selenoproteins and is acquired either through diet or cellular recycling mechanisms. Selenocysteine lyase (Scly) is the enzyme that supplies Se for selenoprotein biosynthesis via decomposition of the amino acid selenocysteine (Sec). Knockout (KO) of Scly in a mouse affected hepatic glucose and lipid homeostasis. Mice lacking Scly and raised on an Se-adequate diet exhibit hyperinsulinemia, hyperleptinemia, glucose intolerance, and hepatic steatosis, with increased hepatic oxidative stress, but maintain selenoprotein levels and circulating Se status. Insulin challenge of Scly KO mice results in attenuated Akt phosphorylation but does not decrease phosphorylation levels of AMP kinase alpha (AMPKα). Upon dietary Se restriction, Scly KO animals develop several characteristics of metabolic syndrome, such as obesity, fatty liver, and hypercholesterolemia, with aggravated hyperleptinemia, hyperinsulinemia, and glucose intolerance. Hepatic glutathione peroxidase 1 (GPx1) and selenoprotein S (SelS) production and circulating selenoprotein P (Sepp1) levels are significantly diminished. Scly disruption increases the levels of insulin-signaling inhibitor PTP1B. Our results suggest a dependence of glucose and lipid homeostasis on Scly activity. These findings connect Se and energy metabolism and demonstrate for the first time a unique physiological role of Scly in an animal model.

Selenoprotein

Selenocysteine

Hyperinsulinemia

Selenoprotein P

Steatosis

GPX1

Selenium deficiency

10.1128/mcb.00293-12

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Citations (112)

PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance

Molecular Cell (2024)

Zhiyi Chen Alex Inague Kamini Kaushal Gholamreza Fazeli Danny Schilling

Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and begins with the uptake of the Sec carrier, selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP is metabolized via selenocysteine lyase (SCLY), producing selenide, a substrate for selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor, selenophosphate (H2SePO3-), for the biosynthesis of the Sec-tRNA. Here, we discovered an alternative pathway in Sec metabolism mediated by peroxiredoxin 6 (PRDX6), independent of SCLY. Mechanistically, we demonstrate that PRDX6 can readily react with selenide and interact with SEPHS2, potentially acting as a selenium delivery system. Moreover, we demonstrate the functional significance of this alternative route in human cancer cells, revealing a notable association between elevated expression of PRDX6 and human MYCN-amplified neuroblastoma subtype. Our study sheds light on a previously unrecognized aspect of Sec metabolism and its implications in ferroptosis, offering further possibilities for therapeutic exploitation.

Selenocysteine

10.1016/j.molcel.2024.10.027

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Citations (4)

Relationship between selenoprotein P and selenocysteine lyase: Insights into selenium metabolism

Free Radical Biology and Medicine (2018)

Lucia A. Seale Herena Y. Ha Ann C. Hashimoto Marla J. Berry

Selenoprotein

Selenocysteine

Selenoprotein P

10.1016/j.freeradbiomed.2018.03.037

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