ABSTRACT
Huntington's disease (HD) is a progressive neurodegenerative illness for which there is no effective therapy. We examined whether creatine, which may exert neuroprotective effects by increasing phosphocreatine levels or by stabilizing the mitochondrial permeability transition, has beneficial effects in a transgenic mouse model of HD (line 6/2). Dietary creatine supplementation significantly improved survival, slowed the development of brain atrophy, and delayed atrophy of striatal neurons and the formation of huntingtin-positive aggregates in R6/2 mice. Body weight and motor performance on the rotarod test were significantly improved in creatine-supplemented R6/2 mice, whereas the onset of diabetes was markedly delayed. Nuclear magnetic resonance spectroscopy showed that creatine supplementation significantly increased brain creatine concentrations and delayed decreases in N-acetylaspartate concentrations. These results support a role of metabolic dysfunction in a transgenic mouse model of HD and suggest a novel therapeutic strategy to slow the pathological process.
Subject(s)
Creatine/therapeutic use , Huntington Disease/drug therapy , Nerve Tissue Proteins/genetics , Neurons/pathology , Neuroprotective Agents/therapeutic use , Nuclear Proteins/genetics , Animals , Animals, Genetically Modified , Aspartic Acid/analogs & derivatives , Aspartic Acid/metabolism , Atrophy , Brain/drug effects , Brain/pathology , Corpus Striatum/drug effects , Corpus Striatum/pathology , Creatine/administration & dosage , Creatine/metabolism , Crosses, Genetic , Dietary Supplements , Female , Humans , Huntingtin Protein , Huntington Disease/pathology , Huntington Disease/physiopathology , Magnetic Resonance Imaging , Male , Mice , Mice, Inbred Strains , Motor Activity/drug effects , Neurons/drug effects , Neuroprotective Agents/administration & dosageABSTRACT
The cornified envelope of keratinocytes is an insoluble structure formed beneath the plasma membrane at the base of the stratum corneum. It is made by cross-linking precursor proteins by a membrane-associated transglutaminase. We have prepared monoclonal antibodies to the cornified envelope of cultured human keratinocytes and used these to identify precursor proteins using Western blotting. We have uncovered a number of precursors including involucrin and a 195 kD membrane-associated protein, which had previously been reported. Antibodies to these precursors, with the exception of the one to involucrin, reacted with the epidermis of other mammalian species, suggesting structural conservation in at least some envelope components.