Role of Selenoprotein P in brain zinc homeostasis

dc.contributor.author Parubrub, Arlene Condaya
dc.date.accessioned 2016-05-02T23:09:33Z
dc.date.available 2016-05-02T23:09:33Z
dc.date.issued 2013-12
dc.description M.S. University of Hawaii at Manoa 2013.
dc.description Includes bibliographical references.
dc.description.abstract Selenoprotein P (Sepp1) is a selenium-rich antioxidant protein involved in extracellular transport of selenium (Se). Sepp1 also has metal binding properties. Zinc (Zn2+) is an essential micronutrient that is released from terminals in the brain that utilize the neurotransmitter, glutamate. Both Zn2+ and Se are necessary for proper brain function. However, intracellular Zn2+ accumulation can contribute to neurotoxicity, and extracellular Zn2+ can promote aggregation of amyloid-beta to form brain plaques during development of Alzheimer's disease (AD). Through metal column purification, we confirmed Sepp1's ability to bind Zn2+ as well as other biometals including Co2+ and Ni2+. We investigated the role of Sepp1 in Zn2+ regulation by examining Zn2+ levels in wildtype (WT) and Sepp1 knockout (Sepp1-/-) mice. Zinc-N-(6-methoxy-8-quinolyl)-ptoluenesulphonamide (TSQ) staining revealed increased levels of intracellular Zn2+ in the Sepp1-/-hippocampus, the region of the brain that is crucial to memory formation, compared to the WT mice. Mass spectrometry analysis of freshly frozen brain samples demonstrated a marked increase in total brain Zn2+ levels in the Sepp1-/-mice. Additionally, levels of key Zn2+-regulating proteins in the brain are affected by the absence of Sepp1, possibly in response to the elevated Zn2+ content. However, live Zn2+ imaging of hippocampal slices with a selective extracellular fluorescent Zn2+ indicator (Fluozin-3) showed that Sepp1-/-mice have impaired Zn2+ release in response KCl-induced neuron depolarization, which may result in memory impairments. Taken together, our findings reveal that Sepp1 plays a crucial role in the maintenance of Zn2+ homeostasis in the hippocampus and for proper brain function. The identification of a naturally occurring Zn2+-chelator regulated by dietary selenium may significantly contribute to the treatment and prevention of AD.
dc.identifier.uri http://hdl.handle.net/10125/100738
dc.language.iso eng
dc.publisher [Honolulu] : [University of Hawaii at Manoa], [December 2013]
dc.relation Theses for the degree of Master of Science (University of Hawaii at Manoa). Molecular Biosciences and Bioengineering.
dc.subject Selenoprotein P
dc.subject brain zinc
dc.subject Alzheimer's disease
dc.subject selenium
dc.title Role of Selenoprotein P in brain zinc homeostasis
dc.type Thesis
dc.type.dcmi Text
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