Selenoproteins are a unique family of
proteins, characterized by the co-translational incorporation of
selenium as
selenocysteine, which play key roles in
antioxidant defense. Among
selenoproteins,
selenoprotein P (Sepp1) is particularly distinctive due to the fact that it contains multiple
selenocysteine residues and has been postulated to act in
selenium transport. Within the brain, Sepp1 delivers
selenium to neurons by binding to the ApoER2 receptor. Upon feeding a
selenium-deficient diet, mice lacking ApoER2 or Sepp1 develop severe neurological dysfunction and exhibit widespread brainstem neurodegeneration, indicating an important role for ApoER2-mediated Sepp1 uptake in normal brain function.
Selenocysteine lyase (Scly) is an
enzyme that plays an important role in
selenium homeostasis, in that it catalyzes the decomposition of
selenocysteine and allows
selenium to be recycled for additional
selenoprotein synthesis. We previously reported that constitutive deletion of Scly results in neurological deficits only when mice are challenged with a low
selenium diet. To gain insight into the relationship between Sepp1 and Scly in
selenium metabolism, we created novel transgenic mice constitutively lacking both genes (Scly(-/-)Sepp1(-/-)) and characterized the neurobehavioral phenotype. We report that deletion of Scly in conjunction with Sepp1 further aggravates the phenotype of Sepp1(-/-) mice, as these mice needed supraphysiological
selenium supplementation to survive, and surviving mice exhibited impaired motor coordination, audiogenic
seizures, and brainstem neurodegeneration. These findings provide the first in vivo evidence that Scly and Sepp1 work cooperatively to maintain
selenoprotein function in the mammalian brain.