Differential effects of the Huntington's disease CAG mutation in striatum and cerebellum are quantitative not qualitative.
Hum Mol Genet
; 20(21): 4258-67, 2011 Nov 01.
Article
en En
| MEDLINE
| ID: mdl-21840924
ABSTRACT
Huntington's disease (HD) involves marked early neurodegeneration in the striatum, whereas the cerebellum is relatively spared despite the ubiquitous expression of full-length mutant huntingtin, implying that inherent tissue-specific differences determine susceptibility to the HD CAG mutation. To understand this tissue specificity, we compared early mutant huntingtin-induced gene expression changes in striatum to those in cerebellum in young Hdh CAG knock-in mice, prior to onset of evident pathological alterations. Endogenous levels of full-length mutant huntingtin caused qualitatively similar, but quantitatively different gene expression changes in the two brain regions. Importantly, the quantitatively different responses in the striatum and cerebellum in mutant mice were well accounted for by the intrinsic molecular differences in gene expression between the striatum and cerebellum in wild-type animals. Tissue-specific gene expression changes in response to the HD mutation, therefore, appear to reflect the different inherent capacities of these tissues to buffer qualitatively similar effects of mutant huntingtin. These findings highlight a role for intrinsic quantitative tissue differences in contributing to HD pathogenesis, and likely to other neurodegenerative disorders exhibiting tissue-specificity, thereby guiding the search for effective therapeutic interventions.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Cerebelo
/
Neostriado
/
Enfermedad de Huntington
/
Expansión de Repetición de Trinucleótido
/
Proteínas de Transporte de Serotonina en la Membrana Plasmática
Tipo de estudio:
Prognostic_studies
/
Qualitative_research
Límite:
Animals
Idioma:
En
Revista:
Hum Mol Genet
Asunto de la revista:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos