RESUMO
Spinocerebellar ataxia type 7 (SCA7) is one member of a growing list of neurodegenerative disorders that are all caused by CAG repeat expansions that produce disease by encoding elongated polyglutamine tracts in a variety of apparently unrelated proteins. In this review, we provide an overview of our efforts to determine the molecular basis of polyglutamine neurotoxicity in SCA7 by modeling this polyglutamine repeat disorder in mice. We discuss how our SCA7 mouse model develops a phenotype that is reminiscent of the retinal and cerebellar disease pathology seen in human patients. All of these findings are considered in the context of numerous other models of polyglutamine disease pathology in mice and other organisms, together with various other in vitro and biochemical studies. We present the competing hypotheses of polyglutamine disease pathogenesis, and explain how our studies of SCA7 brainstem and retinal degeneration using this mouse model have yielded insights into possible mechanisms and pathways of polyglutamine disease pathology. In addition to illustrating how our SCA7 mouse model has allowed us to develop and advance notions of disease pathogenesis, we propose a model of polyglutamine molecular pathology that attempts to integrate the key observations in the field. We close by describing why our SCA7 mouse model should be useful for the next phase of polyglutamine disease research--the development of therapies, and predict that this stage of experimentation will continue to rely heavily on the mouse.
Assuntos
Modelos Animais de Doenças , Proteínas do Tecido Nervoso/genética , Ataxias Espinocerebelares/genética , Expansão das Repetições de Trinucleotídeos/genética , Ataxina-7 , Tronco Encefálico/metabolismo , Tronco Encefálico/patologia , Tronco Encefálico/ultraestrutura , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Peptídeos/genética , Degeneração Retiniana/genética , Degeneração Retiniana/patologia , Ataxias Espinocerebelares/patologiaRESUMO
Both zinc and neuropeptide Y (NPY) have been implicated as playing a role in seizures and feeding behavior. We investigated the hypothesis that zinc could regulate levels of NPY, and found that chronic exposure to 50-100 microM zinc increased levels of cellular NPY in cultured PC12 cells grown in the presence of nerve growth factor. Zinc's effect on NPY was specific, time- and concentration-dependent, and independent of inhibition of NPY release secondary to blockade of dihydropyridine-sensitive calcium channels. These results are consistent with a role for zinc in regulating hippocampal NPY following high-frequency neuronal activity.
