Role of Selenoprotein P in brain zinc homeostasis

Parubrub, Arlene Condaya
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[Honolulu] : [University of Hawaii at Manoa], [December 2013]
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.
M.S. University of Hawaii at Manoa 2013.
Includes bibliographical references.
Selenoprotein P, brain zinc, Alzheimer's disease, selenium
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