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EMBO Mol Med ; 2(9): 349-70, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20665636

RESUMO

Caused by a polyglutamine expansion in the huntingtin protein, Huntington's disease leads to striatal degeneration via the transcriptional dysregulation of a number of genes, including those involved in mitochondrial biogenesis. Here we show that transglutaminase 2, which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes; transglutaminase 2 interacts directly with histone H3 in the nucleus. In a cellular model of HD, transglutaminase inhibition de-repressed two established regulators of mitochondrial function, PGC-1alpha and cytochrome c and reversed susceptibility of human HD cells to the mitochondrial toxin, 3-nitroproprionic acid; however, protection mediated by transglutaminase inhibition was not associated with improved mitochondrial bioenergetics. A gene microarray analysis indicated that transglutaminase inhibition normalized expression of not only mitochondrial genes but also 40% of genes that are dysregulated in HD striatal neurons, including chaperone and histone genes. Moreover, transglutaminase inhibition attenuated degeneration in a Drosophila model of HD and protected mouse HD striatal neurons from excitotoxicity. Altogether these findings demonstrate that selective TG inhibition broadly corrects transcriptional dysregulation in HD and defines a novel HDAC-independent epigenetic strategy for treating neurodegeneration.


Assuntos
Proteínas de Ligação ao GTP/antagonistas & inibidores , Doença de Huntington/enzimologia , Doença de Huntington/genética , Transcrição Gênica , Transglutaminases/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Citocromos c/genética , Citocromos c/metabolismo , Modelos Animais de Doenças , Drosophila , Metabolismo Energético , Inibidores Enzimáticos/farmacologia , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Histonas/metabolismo , Humanos , Doença de Huntington/metabolismo , Camundongos , Mitocôndrias/metabolismo , Nitrocompostos/toxicidade , Peptídeos/farmacologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Regiões Promotoras Genéticas , Propionatos/toxicidade , Proteína 2 Glutamina gama-Glutamiltransferase , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transglutaminases/genética , Transglutaminases/metabolismo
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