Regional and cellular gene expression changes in human Huntington's disease brain
Open accessAbstract
Huntington's disease (HD) pathology is well understood at a histological level but a comprehensive molecular analysis of the effect of the disease in the human brain has not previously been available. To elucidate the molecular phenotype of HD on a genome-wide scale, we compared mRNA profiles from 44 human HD brains with those from 36 unaffected controls using microarray analysis. Four brain regions were analyzed: caudate nucleus, cerebellum, prefrontal association cortex [Brodmann's area 9 (BA9)] and motor cortex [Brodmann's area 4 (BA4)]. The greatest number and magnitude of differentially expressed mRNAs were detected in the caudate nucleus, followed by motor cortex, then cerebellum. Thus, the molecular phenotype of HD generally parallels established neuropathology. Surprisingly, no mRNA changes were detected in prefrontal association cortex, thereby revealing subtleties of pathology not previously disclosed by histological methods. To establish that the observed changes were not simply the result of cell loss, we examined mRNA levels in laser-capture microdissected neurons from Grade 1 HD caudate compared to control. These analyses confirmed changes in expression seen in tissue homogenates; we thus conclude that mRNA changes are not attributable to cell loss alone. These data from bona fide HD brains comprise an important reference for hypotheses related to HD and other neurodegenerative diseases.
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One molecular phenotype in Huntington's disease patients is transcriptional misregulation in striatum and distinct cortical regions.
“One of the molecular phenotypes in HD patients is transcriptional misregulation in striatum and distinct cortical regions (Hodges et al., 2006).”
From The Bifunctional microRNA miR-9/miR-9* Regulates REST and CoREST and Is Downregulated in Huntington's Disease (2008) · cites this paper as Hodges et al., 2006
The Abstract (page not provided) reports altered mRNA expression in the caudate nucleus and motor cortex of human HD brains. It also reports no detected mRNA changes in the prefrontal association cortex, so the claim overstates the evidence if “distinct cortical regions” means multiple affected cortical regions. (LLM, conf=0.85)
Experimental — accuracy not yet measuredREST mRNA levels do not change significantly in Huntington's disease.
“This may reflect a dedifferentiation mediated by aberrant REST localization, since REST mRNA levels do not change significantly in HD (Hodges et al., 2006), as well as global changes in miR-9/9* and miR-124a target levels.”
From The Bifunctional microRNA miR-9/miR-9* Regulates REST and CoREST and Is Downregulated in Huntington's Disease (2008) · cites this paper as Hodges et al., 2006
The ‘Regional differences and similarities in gene expression within HD brains’ section reports changes across brain regions, but does not give a result for REST mRNA. Searches for REST, NRSF, and RE1-silencing transcription factor found no passage establishing whether REST mRNA changes significantly in HD. (LLM, conf=0.74)
Experimental — accuracy not yet measuredComparison of activation z-scores of significantly overrepresented pathways in human control versus Huntington's disease caudate to those in control versus R6/2 striatal tissue found concordance between the mouse model and the human disease.
“We compared the activation z -scores of significantly overrepresented pathways in human control versus Huntington's disease caudate [ z -score overall = 41.23; gene expression data taken from Hodges et al. , (2006)] to those in control versus R6/2 striatal tissue and found concordance between the mouse model and the human disease (Fig. 3D).”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Hodges et al., 2006
Human striatal samples analyzed for pathways showed higher astrocyte and CSPG mRNA in disease.
“Importantly, the same human striatal samples used for pathway analysis also displayed elevated astrocyte and CSPG mRNA with disease (Hodges et al. , 2006).”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Hodges et al. , 2006
Genes related to neurogenesis are highly overrepresented amongst the genes changed in expression in the cortex (BA4) of Huntington's disease patients.
“Interestingly, genes related to neurogenesis are highly overrepresented amongst the genes changed in expression in the cortex (BA4) of HD patients (Hodges et al., 2006).”
From The Bifunctional microRNA miR-9/miR-9* Regulates REST and CoREST and Is Downregulated in Huntington's Disease (2008) · cites this paper as Hodges et al., 2006
Brodmann's area 4 cortex was chosen because prior work indicates widespread transcriptional changes in this region in Huntington's disease patients.
“We specifically chose Brodmann’s area 4 (BA4) cortex because prior work indicates widespread transcriptional changes in this region in HD patients (Hodges et al., 2006).”
From The Bifunctional microRNA miR-9/miR-9* Regulates REST and CoREST and Is Downregulated in Huntington's Disease (2008) · cites this paper as Hodges et al., 2006
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References 46 · Cited by 804
Research works printed but not linked: 1
- Gutekunst, C.A., Norflus, F. and Hersch, S.M. (2002) The neuropathology of Huntington's disease. In Bates, G.P., Harper, P.S. and Jones, A.L. (eds), Huntington's Disease, 4th edn. OUP, Oxford, UK, pp. 251-275.
- Authors
- Hodges, A., Strand, A. D., Aragaki, A. K., Kuhn, A., Sengstag, T., Hughes, G., Elliston, L. A., Hartog, C., Goldstein, D. R., Thu, D., Hollingsworth, Z. R., Collin, F., Synek, B., Holmans, P. A., Young, A. B., Wexler, N. S., Delorenzi, M., Kooperberg, C., Augood, S. J., Faull, R. L. M., Olson, J. M., Jones, L., & Luthi-Carter, R.
- Affiliations
- Cardiff University (GB)
- Fred Hutch Cancer Center (US)
- École Polytechnique Fédérale de Lausanne (CH)
- SIB Swiss Institute of Bioinformatics (CH)
- University of Auckland (NZ)
- Massachusetts General Hospital (US)
- Auckland City Hospital (NZ)
- Hereditary Disease Foundation (US)
- Corresponding author
- Hodges, Angela
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-02-08
- Volume
- 15
- Issue
- 6
- Pages
- 965-977
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2160748841
- Cited by
- 804
- References
- 46
- Citations by year
- 2026: 23 · 2025: 27 · 2024: 35 · 2023: 35 · 2022: 41 · 2021: 61 · 2020: 47 · 2019: 28 · 2018: 49 · 2017: 48 · 2016: 43 · 2015: 35 · 2014: 53 · 2013: 33 · 2012: 59
- FWCI
- 13.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- reroDoc Digital Library (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- IRIS (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Science Foundation
- Hereditary Disease Foundation
- Massachusetts General Hospital
- Cure Huntington's Disease Initiative
- Novartis Foundation
- Parc Geneteg Cymru
- Cardiff University
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health
- Directorate for Biological Sciences
- Medical Research Council
- Health Research Council of New Zealand
- National Cancer Institute (CA74841)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Keywords
- Huntington's disease, gene expression profiling, differentially expressed mRNAs, caudate nucleus, cerebellum, motor cortex, laser capture microdissection, cell loss, molecular phenotypes, neurodegeneration
- MeSH terms
- Adult, Aged, Axons, Brain, Female, Humans, Huntington Disease, Male, Middle Aged, RNA, Messenger, Signal Transduction, Cell Death, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling
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