Mice Lacking Selenoprotein P and Selenocysteine Lyase Exhibit Severe Neurological Dysfunction, Neurodegeneration, and Audiogenic Seizures

Byrns, China N.; Pitts, Michael R.; Gilman, Christy; Hashimoto, Ann C.; Berry, Marla J.

doi:10.1074/jbc.m113.540682

Cited by 54 publications

(51 citation statements)

References 39 publications

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“…The canonical pathways significantly affected by AC-T treatment were molybdenum biosynthesis and selenocysteine biosynthesis which are both involved in redox reactions [33,34]. Fatty acid activation was also affected which can occur in the outer mitochondrial membrane.…”

Section: Discussionmentioning

confidence: 99%

Assessing the Effects of Redox Modifier MnTnBuOE-2-PyP 5+ on Cognition and Hippocampal Physiology Following Doxorubicin, Cyclophosphamide, and Paclitaxel Treatment

McElroy

Brown

Kiffer

et al. 2020

IJMS

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Background: Chemotherapy treatment for breast cancer can induce cognitive impairments often involving oxidative stress. The brain, as a whole, is susceptible to oxidative stress due to its high-energy requirements, limited anaerobic respiration capacities, and limited antioxidant defenses. The goal of the current study was to determine if the manganese porphyrin superoxide dismutase mimetic MnTnBuOE-2-PyP (MnBuOE) could ameliorate the effects of doxorubicin, cyclophosphamide, and paclitaxel (AC-T) on mature dendrite morphology and cognitive function. Methods: Four-month-old female C57BL/6 mice received intraperitoneal injections of chemotherapy followed by subcutaneous injections of MnBuOE. Four weeks following chemotherapy treatment, mice were tested for hippocampus-dependent cognitive performance in the Morris water maze. After testing, brains were collected for Golgi staining and molecular analyses. Results: MnBuOE treatment preserved spatial memory during the Morris water-maze. MnBuOE/AC-T showed spatial memory retention during all probe trials. AC-T treatment significantly impaired spatial memory retention in the first and third probe trial (no platform). AC-T treatment decreased dendritic length in the Cornu Ammonis 1 (CA1) and dentate gyrus (DG) areas of the hippocampus while AC-T/MnBuOE maintained dendritic length. Comparative proteomic analysis revealed affected protein networks associated with cell morphology and behavior functions in both the AC-T and AC-T/MnBuOE treatment groups.

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Section: Discussionmentioning

confidence: 99%

Assessing the Effects of Redox Modifier MnTnBuOE-2-PyP 5+ on Cognition and Hippocampal Physiology Following Doxorubicin, Cyclophosphamide, and Paclitaxel Treatment

McElroy

Brown

Kiffer

et al. 2020

IJMS

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“…Selenocysteine lyase-knockout mice are viable when fed diets that are not severely selenium deficient (92). However, mice with selenium deficiency in their brains, caused by knockout of the selenium transport protein Sepp1 (45,90), develop severe neurological injury and die when selenocysteine lyase is knocked out simultaneously (23). Thus, selenocysteine lyase protects brain neurons under selenium-deficient conditions, presumably by facilitating reutilization of their selenium (Figure 2).…”

Section: The Intracellular Selenium Cyclementioning

confidence: 95%

Regulation of Selenium Metabolism and Transport

2015

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Selenium is regulated in the body to maintain vital selenoproteins and to avoid toxicity. When selenium is limiting, cells utilize it to synthesize the selenoproteins most important to them, creating a selenoprotein hierarchy in the cell. The liver is the central organ for selenium regulation and produces excretory selenium forms to regulate whole-body selenium. It responds to selenium deficiency by curtailing excretion and secreting selenoprotein P (Sepp1) into the plasma at the expense of its intracellular selenoproteins. Plasma Sepp1 is distributed to tissues in relation to their expression of the Sepp1 receptor apolipoprotein E receptor-2, creating a tissue selenium hierarchy. N-terminal Sepp1 forms are taken up in the renal proximal tubule by another receptor, megalin. Thus, the regulated whole-body pool of selenium is shifted to needy cells and then to vital selenoproteins in them to supply selenium where it is needed, creating a whole-body selenoprotein hierarchy. 17.1

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“…Another line of evidence has demonstrated that oxidative stress impairs PV-interneuron development and functionality [66, 67, 160]. Along a similar vein, several studies in selenoprotein knockout mice have reported deficits in PV-interneurons [65, 68, 113], presumably due to diminished antioxidant defense capabilities. Moreover, a microarray study examining gene expression in postmortem prefrontal cortex tissue found that SelP levels were significantly lower in subjects with schizophrenia [161].…”

Section: Selenium Selenoproteins and Neurological Diseasementioning

confidence: 98%

“…These results suggest that Scly-mediated Sec recycling becomes physiologically important only when dietary Se supply is not adequate. To obtain insight into the relationship between Scly and SelP in selenium metabolism, double knockout mice lacking both of the aforementioned genes were generated and characterized [113]. Scly −/− SelP −/− mice required selenium supplementation to survive, and surviving mice exhibited impaired motor coordination, audiogenic seizures, and neurodegeneration in brainstem regions akin to those previously reported for ApoER2 −/− and SelP −/− mice fed Se-deficient diets [90].…”

Section: Constitutive Knockout Mice Studiesmentioning

confidence: 99%

Selenoproteins in Nervous System Development and Function

Pitts

Byrns

Ogawa-Wong

et al. 2014

Biol Trace Elem Res

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Selenoproteins are a distinct class of proteins that are characterized by the co-translational incorporation of selenium (Se) in the form of the 21st amino acid selenocysteine. Selenoproteins provide a key defense against oxidative stress, as many of these proteins participate in oxidation-reduction reactions neutralizing reactive oxygen species, where selenocysteine residues act as catalytic sites. Many selenoproteins are highly expressed in the brain and mouse knockout studies have determined that several are required for normal brain development. In parallel with these laboratory studies, recent reports of rare human cases with mutations in genes involved in selenoprotein biosynthesis have described individuals with an assortment of neurological problems that mirror those detailed in knockout mice. These deficits include impairments in cognition and motor function, seizures, hearing loss, and altered thyroid metabolism. Additionally, due to the fact that oxidative stress is a key feature of neurodegenerative disease, there is considerable interest in the therapeutic potential of selenium supplementation for human neurological disorders. Studies performed in cell culture and rodent models have demonstrated that selenium administration attenuates oxidative stress, prevents neurodegeneration, and counters cell signaling mechanisms known to be dysregulated in certain disease states. However, there is currently no definitive evidence in support of selenium supplementation to prevent and/or treat common neurological conditions in the general population. It appears likely, that in humans, supplementation with selenium may only benefit certain subpopulations, such as those that are either selenium-deficient or possess genetic variants that affect selenium metabolism.

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Mice Lacking Selenoprotein P and Selenocysteine Lyase Exhibit Severe Neurological Dysfunction, Neurodegeneration, and Audiogenic Seizures

Cited by 54 publications

References 39 publications

Assessing the Effects of Redox Modifier MnTnBuOE-2-PyP 5+ on Cognition and Hippocampal Physiology Following Doxorubicin, Cyclophosphamide, and Paclitaxel Treatment

Assessing the Effects of Redox Modifier MnTnBuOE-2-PyP 5+ on Cognition and Hippocampal Physiology Following Doxorubicin, Cyclophosphamide, and Paclitaxel Treatment

Regulation of Selenium Metabolism and Transport

Selenoproteins in Nervous System Development and Function

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