Mutant huntingtin gene-dose impacts on aggregate deposition, DARPP32 expression and neuroinflammation in HdhQ150 mice.
PLoS One
; 8(9): e75108, 2013.
Article
em En
| MEDLINE
| ID: mdl-24086450
ABSTRACT
Huntington's disease (HD) is an autosomal dominant, progressive and fatal neurological disorder caused by an expansion of CAG repeats in exon-1 of the huntingtin gene. The encoded poly-glutamine stretch renders mutant huntingtin prone to aggregation. HdhQ150 mice genocopy a pathogenic repeat (â¼150 CAGs) in the endogenous mouse huntingtin gene and model predominantly pre-manifest HD. Treating early is likely important to prevent or delay HD, and HdhQ150 mice may be useful to assess therapeutic strategies targeting pre-manifest HD. This requires appropriate markers and here we demonstrate, that pre-symptomatic HdhQ150 mice show several dramatic mutant huntingtin gene-dose dependent pathological changes including (i) an increase of neuronal intra-nuclear inclusions (NIIs) in brain, (ii) an increase of extra-nuclear aggregates in dentate gyrus, (iii) a decrease of DARPP32 protein and (iv) an increase in glial markers of neuroinflammation, which curiously did not correlate with local neuronal mutant huntingtin inclusion-burden. HdhQ150 mice developed NIIs also in all retinal neuron cell-types, demonstrating that retinal NIIs are not specific to human exon-1 R6 HD mouse models. Taken together, the striking and robust mutant huntingtin gene-dose related changes in aggregate-load, DARPP32 levels and glial activation markers should greatly facilitate future testing of therapeutic strategies in the HdhQ150 HD mouse model.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Nucleares
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Regulação da Expressão Gênica
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Doença de Huntington
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Dosagem de Genes
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Modelos Animais de Doenças
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Fosfoproteína 32 Regulada por cAMP e Dopamina
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Proteínas do Tecido Nervoso
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article