␣-Tocopherol transfer protein (␣-TTP) maintains the concentration of serum ␣-tocopherol (vitamin E), one of the most potent fat-soluble antioxidants, by facilitating ␣-tocopherol export from the liver. Mutations of the ␣-TTP gene are linked to ataxia with isolated vitamin E deficiency (AVED). We produced a model mouse of AVED by deleting the ␣-TTP gene, which showed ataxia and retinal degeneration after 1 year of age. Because the brain ␣-TTP functions in maintaining ␣-tocopherol levels in the brain, ␣-tocopherol was completely depleted in the ␣-TTP ؊͞؊ mouse brain, and the neurological phenotype of ␣-TTP ؊͞؊ mice is much more severe than that of wild-type mice when maintained on an ␣-tocopherol-deficient diet. Lipid peroxidation in ␣-TTP ؊͞؊ mice brains showed a significant increase, especially in degenerating neurons. ␣-Tocopherol supplementation suppressed lipid peroxidation and almost completely prevented the development of neurological symptoms. This therapy almost completely corrects the abnormalities in a mouse model of human neurodegenerative disease. Moreover, ␣-TTP ؊͞؊ mice may prove to be excellent animal models of delayed onset, slowly progressive neuronal degeneration caused by chronic oxidative stress.A taxia with isolated vitamin E deficiency (AVED) is an autosomal recessive disease, the phenotype of which is often indistinguishable from Friedreich ataxia (1), the most common hereditary ataxia in Europe and United States. We cloned the ␣-tocopherol transfer protein (␣-TTP) gene (2) and identified mutations on the ␣-TTP gene in patients with AVED (3, 4). Later, we found those same mutations on the ␣-TTP gene to be a cause of retinitis pigmentosa as well (5, 6). ␣-TTP is expressed in the brain and retina as well as in the liver, and its function still remains unclear (6, 7). Therefore, it is not known whether ␣-tocopherol deficiency is the only cause for neuronal degeneration of AVED. Here we produced a model mouse of AVED by deleting the ␣-TTP gene. The mice showed ataxia and retinal degeneration after 1 year of age, and these symptoms were reversed after ␣-tocopherol supplementation.The brain is thought to be particularly vulnerable to oxidative stress (8), and accumulating evidence suggests that oxidative stress is involved in the pathogenesis of neurodegenerative diseases including Alzheimer's disease and amyotrophic lateral sclerosis (8,9). In animal models, neuronal cell death has been induced by free radical-producing chemicals, such as paraquat (10) or N-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; ref. 11), or by knocking out the manganese superoxide dismutase gene (12). These experimentally induced neuronal degenerations develop acutely within several days and differ therefore from the cell death that occurs in human neurodegenerative diseases, which are characterized by delayed onset and slow progression over years or decades. We discuss whether the ␣-TTP Ϫ͞Ϫ mouse serves as a mouse model of age-related neuronal degeneration arising from chronic oxidative stress. Materials and MethodsG...

␣-Tocopherol transfer protein (␣-TTP), a cytosolic protein that specifically binds ␣-tocopherol, is known as a product of the causative gene in patients with ataxia that is associated with vitamin E deficiency. Targeted disruption of the ␣-TTP gene revealed that ␣-tocopherol concentration in the circulation was regulated by ␣-TTP expression levels. Male ␣-TTP ؊/؊ mice were fertile; however, placentas of pregnant ␣-TTP ؊/؊ females were severely impaired with marked reduction of labyrinthine trophoblasts, and the embryos died at mid-gestation even when fertilized eggs of ␣-TTP ؉/؉ mice were transferred into ␣-TTP ؊/؊ recipients. The use of excess ␣-tocopherol or a synthetic antioxidant (BO-653) dietary supplement by ␣-TTP ؊/؊ females prevented placental failure and allowed full-term pregnancies. In ␣-TTP ؉/؉ animals, ␣-TTP gene expression was observed in the uterus, and its level transiently increased after implantation (4.5 days postcoitum). Our results suggest that oxidative stress in the labyrinth region of the placenta is protected by vitamin E during development and that in addition to the hepatic ␣-TTP, which governs plasma ␣-tocopherol level, the uterine ␣-TTP may also play an important role in supplying this vitamin.Vitamin E (␣-tocopherol) is the most potent lipid-soluble antioxidant in biological membranes, where it contributes to membrane stability. Patients with ataxia and isolated vitamin E deficiency (AVED) 1 have low or undetectable serum vitamin E concentrations and exhibit neurological dysfunction and muscular weakness. It is now established that ␣-tocopherol transfer protein (␣-TTP), a cytosolic liver protein known to specifically bind to ␣-tocopherol (1), is defective in AVED patients (2), indicating that ␣-TTP is a major determinant of plasma ␣-tocopherol level. Although ␣-tocopherol was initially identified as an anti-sterility factor to prevent abortion (3), the mechanism of action and the molecules responsible for its antisterility effect remain unknown. One of the reasons for this is that vitamin E is difficult to deplete from tissues and requires elaborate manipulations to cause deficiency symptoms to occur in experimental animals. In this study, we established a mouse model lacking ␣-TTP by targeted mutagenesis. This animal model for human AVED patients is suitable for examination of the complex pathophysiology of diseases associated with vitamin E deficiency and/or caused by oxidative stress. Here we examined the role of ␣-TTP in pregnancy and embryogenesis using our new animal model. MATERIALS AND METHODSGeneration of ␣-TTP Knockout Mice-An ␣-TTP targeting vector was constructed from an 8.8-kb ␣-TTP genome fragment encompassing exon 1. We inserted a fragment of PGK-neo cassette into the SmaI-SmaI site positioned 5Ј and 3Ј to exon 1 and flanked a 1.8-kb fragment of HSV-tk gene downstream of exon 2. AB2.2-Prime ES cells (Lexicon Genetics) or A3-1 ES (4) cells were transfected by electroporation with a linearized targeting vector. G418/gancyclovir-resistant clones were screened by PCR, and...

Alpha-tocopherol transfer protein (alpha-TTP) was first described to play a major role in maintaining alpha-tocopherol levels in plasma, while alpha-tocopherol was primarily reported to be a factor relevant for reproduction. Expression of alpha-TTP is not only seen in the liver, from where it was first isolated, but also in mouse uterus, depending on its state of pregnancy, stressing the importance of alpha-TTP for embryogenesis and fetal development. The cellular localization of alpha-TTP in mouse uterus is reported here. By immunohistochemistry, alpha-TTP could be localized in the secretory columnar epithelial cells of the pregnant uterus on Days 4.5 and 6.5 postcoitum as well as in the glandular epithelial cells and the inner decidual reaction zone surrounding the implantation site. On Days 8.5 and 10.5 postcoitum (midterm of mouse pregnancy), alpha-TTP could still be detected in the uterine secretory columnar epithelial cells, while in alpha-TTP knockout mice, no immunostaining was visible. It is suggested that alpha-TTP plays a major role in supplying the placenta and consecutively the fetus with alpha-tocopherol throughout pregnancy. We conclude that alpha-tocopherol plays a role in the process of implantation and that alpha-TTP may be necessary for adequate alpha-tocopherol status of the fetus.

The purpose of this study was to examine if there is a human jaw-tongue reflex. This study was carried out in seven healthy adult males and recorded the genioglossus muscle activity during various functions by using a miniature intraoral surface electrode, which is comparable with intramuscular fine-wire electrodes, but without pain or disturbance of the tongue movement. The ipsilateral masseteric and digastric muscle activities were simultaneously recorded with the surface electrodes. Tonic genioglossus muscle activity was recorded during clenching. A passive jaw opening elicited the stretch reflex in the masseteric muscle and increased genioglossus muscle activity. Electrical stimulation of the lower lip inhibited the tonic activity in the masseteric and genioglossus muscles during both clenching and tongue protrusion. Moreover, the latency of the inhibition in the genioglossus muscle activity was shorter during clenching than during tongue protrusion. Based on these findings, the authors conclude that the human jaw-tongue reflex exists and that the jaw-closing muscle is involved in evoking the reflex.