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DNA Research Advance Access published online on May 23, 2007
DNA Research, doi:10.1093/dnares/dsm007
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© The Author 2007. Kazusa DNA Research Institute
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Merging Mouse Transcriptome Analyses with Parkinson's Disease Linkage Studies

Daniel Gherbassi, Lavinia Bhatt, Sandrine Thuret {dagger} and Horst H. Simon*

Department of Neuroanatomy, Interdisciplinary Center for Neuroscience, University of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany

Received 5 September 2006 ; revised 26 March 2007

The hallmark of Parkinson's disease (PD OMIM #168600) is the degeneration of the nigral dopaminergic system affecting approximately 1% of the human population older than 65. In pursuit of genetic factors contributing to PD, linkage and association studies identified several susceptibility genes. The majority of these genes are expressed by the dopamine-producing neurons in the substantia nigra. We, therefore, propose expression by these neurons as a selection criterion, to narrow down, in a rational manner, the number of candidate genes in orphan PD loci, where no mutation has been associated thus far. We determined the corresponding human chromosome locations of 1435 murine cDNA fragments obtained from murine expression analyses of nigral dopaminergic neurons and combined these data with human linkage studies. These fragments represent 19 genes within orphan OMIM PD loci. We used the same approach for independent association studies and determined the genes in neighborhood to the peaks with the highest LOD score value. Our approach did not make any assumptions about disease mechanisms, but it, nevertheless, revealed {alpha}-synuclein, NR4A2 (Nurr1), and the tau genes, which had previously been associated to PD. Furthermore, our transcriptome analysis identified several classes of candidate genes for PD mutations and may also provide insight into the molecular pathways active in nigral dopaminergic neurons.

Key words: dopaminergic neurons; substantia nigra; neurodegenerative disease; candidate genes

* To whom correspondence should be addressed. Tel. +49-6221-548342. Fax. +49-6221-545605. E-mail: horst.simon{at}urz.uni-heidelberg.de

Communicated by Shoji Tsuji

{dagger} Present address: King's College London, Centre for the Cellular Basis of Behaviour, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, P039, 1-2 WW Ground, Denmark Hill, London SE5 8AF, UK.


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