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Human Molecular Genetics Advance Access originally published online on February 8, 2006
Human Molecular Genetics 2006 15(6):965-977; doi:10.1093/hmg/ddl013
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Regional and cellular gene expression changes in human Huntington's disease brain

Angela Hodges1,2,{dagger}, Andrew D. Strand3, Aaron K. Aragaki3, Alexandre Kuhn4, Thierry Sengstag5, Gareth Hughes1,2, Lyn A. Elliston1,2, Cathy Hartog2, Darlene R. Goldstein4, Doris Thu6, Zane R. Hollingsworth7, Francois Collin8, Beth Synek9, Peter A. Holmans1, Anne B. Young7, Nancy S. Wexler10,11, Mauro Delorenzi5, Charles Kooperberg3, Sarah J. Augood7, Richard L.M. Faull6, James M. Olson3,{ddagger}, Lesley Jones1,2,{ddagger} and Ruth Luthi-Carter4,*,{ddagger}

1Department of Psychological Medicine and 2Department of Medical Genetics, Wales College of Medicine and School of Biosciences, Cardiff University, Heath Park, Cardiff CF14 4XN, Wales, UK, 3Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA, 4Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland, 5National Center of Competence in Research (NCCR) Molecular Oncology, Swiss Institute of Experimental Cancer Research (ISREC) and Swiss Institute of Bioinformatics (SIB), CH-1015 Lausanne, Switzerland, 6Department of Anatomy with Radiology, University of Auckland, Private Bag 92019, Auckland, New Zealand, 7MassGeneral Institute of Neurodegenerative Disease (MIND), Massachusetts General Hospital, Charlestown, MA 02129, USA, 8Department of Statistics, University of California, Berkeley, CA 94720-3860, USA, 9Auckland City Hospital, Auckland, New Zealand, 10Columbia University, New York, NY 10032, USA and 11Hereditary Disease Foundation, Santa Monica, CA 90405, USA

* To whom correspondence should be addressed at: Laboratory of Functional Neurogenomics AI 2138, Ecole Polytechnique Fédérale de Lausanne (EPFL), Station 15, CH-1015 Lausanne, Switzerland. Tel:+41 216939533; Fax: +41 216939628; Email: ruth.luthi-carter{at}epfl.ch

Received December 5, 2005; Accepted February 1, 2006

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.

{dagger} Present address: MRC Centre for Neurodegeneration Research, Department of Psychological Medicine, Box PO 70, Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, UK.

{ddagger} The authors wish it to be known that, in their opinion, the last three authors should be regarded as joint Senior Authors.


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