Alterations in Ca 2+ homeostasis and accumulation of unfolded proteins in the endoplasmic reticulum (ER) lead to an ER stress response. Prolonged ER stress may lead to cell death. Glucose-regulated protein (GRP) 78 (Bip) is an ER lumen protein whose expression is induced during ER stress. GRP78 is involved in polypeptide translocation across the ER membrane, and also acts as an apoptotic regulator by protecting the host cell against ER stress-induced cell death, although the mechanism by which GRP78 exerts its cytoprotective effect is not understood. The present study was carried out to determine whether one of the mechanisms of cell death inhibition by GRP78 involves inhibition of caspase activation. Our studies indicate that treatment of cells with ER stress inducers causes GRP78 to redistribute from the ER lumen with subpopulations existing in the cytosol and as an ER transmembrane protein. GRP78 inhibits cytochrome c-mediated caspase activation in a cell-free system, and expression of GRP78 blocks both caspase activation and caspase-mediated cell death. GRP78 forms a complex with caspase-7 and -12 and prevents release of caspase-12 from the ER. Addition of (d)ATP dissociates this complex and may facilitate movement of caspase-12 into the cytoplasm to set in motion the cytosolic component of the ER stressinduced apoptotic cascade. These results define a novel protective role for GRP78 in preventing ER stress-induced cell death. ß 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.

Mutation in Cu/Zn-superoxide dismutase (SOD1) is a cause of familial amyotrophic lateral sclerosis (ALS).[Keywords: Amyotrophic lateral sclerosis; endoplasmic reticulum-associated degradation; endoplasmic reticulum stress; Derlin-1; ASK1] Supplemental material is available at http://www.genesdev.org.

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␣-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...