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Published on: March 11, 2020
Differential effects of the Huntington's disease CAG mutation in striatum and cerebellum are quantitative not
Elisa Fossale1, Ihn Sik Seong, Kathryn R Coser
1Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
Insights
Huntington's disease (HD) shows tissue-specific effects due to inherent molecular differences. The brain's striatum and cerebellum respond differently to mutant huntingtin, influencing disease progression.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington's disease (HD) causes early striatal neurodegeneration, while the cerebellum is relatively spared.
- Ubiquitous expression of mutant huntingtin suggests tissue-specific factors dictate disease susceptibility.
- Understanding these differences is key to explaining HD's selective pathology.
Purpose of the Study:
- To investigate the tissue-specific gene expression changes induced by mutant huntingtin in the striatum versus the cerebellum.
- To determine if intrinsic molecular differences between these brain regions contribute to Huntington's disease (HD) pathogenesis.
- To elucidate the mechanisms underlying the differential susceptibility of brain tissues to the HD CAG mutation.
Main Methods:
- Comparison of early gene expression changes in the striatum and cerebellum of young Hdh CAG knock-in mice.
- Analysis of endogenous full-length mutant huntingtin effects prior to observable pathological alterations.
- Assessment of intrinsic molecular differences in gene expression between wild-type striatum and cerebellum.
Main Results:
- Mutant huntingtin induced qualitatively similar but quantitatively different gene expression changes in the striatum and cerebellum.
- These quantitative differences were largely explained by the inherent molecular distinctions between the two brain regions in wild-type mice.
- The striatum and cerebellum exhibit different capacities to buffer the effects of mutant huntingtin.
Conclusions:
- Tissue-specific gene expression changes in HD reflect the intrinsic buffering capacities of different brain regions.
- Intrinsic quantitative molecular differences play a significant role in Huntington's disease (HD) pathogenesis.
- These findings have implications for understanding and treating other neurodegenerative disorders with tissue specificity.
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.
