Neurodegeneration in mice resulting from loss of functional selenoprotein P or its receptor apolipoprotein E receptor 2.
Selenoprotein P (Sepp1) is involved in selenium homeostasis. Mice with a deletion of Sepp1, replacement of it by the shortened form Sepp1(Delta240-361), or deletion of its receptor apolipoprotein E receptor 2 develop severe neurologic dysfunction when fed low-selenium diet. Because the brainstems of Sepp1(-/-) mice had been observed to contain degenerated axons, a study of these 3 strains was made under selenium-deficient and high-selenium (control) conditions. Selenium-deficient wild-type mice were additional controls. Serial sections of the brain were evaluated with amino cupric silver degeneration and anti-glial fibrillary acidic protein stains. All 3 strains with altered Sepp1 metabolism developed severe axonal injury when fed selenium deficient diet. This injury was mitigated by high-selenium diet and was absent from selenium-deficient wild-type mice. Injury was most severe in Sepp1(-/-) mice, with staining in at least 6 brain regions. Injury in Sepp1(Delta240-361) and apolipoprotein E receptor 2 mice was less severe and occurred only in areas injured in Sepp1(-/-) mice, suggesting a common selenium-related etiology. Affected brain regions were primarily associated with auditory and motor functions, consistent with the clinical signs. Those areas have high metabolic rates. We conclude that interference with Sepp1 function damages auditory and motor areas, at least in part by restricting selenium supply to the brain regions.
Valentine
William M
WM
Department of Pathology, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0252, USA.
Abel
Ty W
TW
Hill
Kristina E
KE
Austin
Lori M
LM
Burk
Raymond F
RF
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D017353:Gene Deletion; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D021621:Imaging, Three-Dimensional / Q000379:methods; D026502:LDL-Receptor Related Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D018110:Receptors, Lipoprotein / Q000172:deficiency*; D051149:Selenoprotein P / Q000172:deficiency* / Q000235:genetics; D016622:Silver Staining / Q000379:methods
D005904:Glial Fibrillary Acidic Protein; D026502:LDL-Receptor Related Proteins; D018110:Receptors, Lipoprotein; D051149:Selenoprotein P; C098773:low density lipoprotein receptor-related protein 8