Differential effects of the Huntington's disease CAG mutation in striatum and cerebellum are quantitative not qualitative

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....

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Bibliographic Details
Published in:Human molecular genetics 2011-11, Vol.20 (21), p.4258-4267
Main Authors: Fossale, Elisa, Seong, Ihn Sik, Coser, Kathryn R., Shioda, Toshi, Kohane, Isaac S., Wheeler, Vanessa C., Gusella, James F., MacDonald, Marcy E., Lee, Jong-Min
Format: Article
Language:English
Subjects:
Animals
Astrocytes - metabolism
Astrocytes - pathology
Ataxin-1
Ataxins
Biological and medical sciences
Biomarkers - metabolism
Cerebellum - metabolism
Cerebellum - pathology
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation
Gene Knock-In Techniques
Genetics of eukaryotes. Biological and molecular evolution
Huntington Disease - genetics
Huntington Disease - pathology
Medical sciences
Mice
Models, Biological
Molecular and cellular biology
Mutant Proteins - metabolism
Neostriatum - metabolism
Neostriatum - pathology
Nerve Tissue Proteins - metabolism
Neurology
Neurons - metabolism
Neurons - pathology
Nuclear Proteins - metabolism
Organ Specificity - genetics
RNA, Messenger - genetics
RNA, Messenger - metabolism
Serotonin Plasma Membrane Transport Proteins - genetics
Serotonin Plasma Membrane Transport Proteins - metabolism
Signal Transduction - genetics
Trinucleotide Repeat Expansion - genetics
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Summary: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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddr355