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Human Molecular Genetics Advance Access originally published online on August 5, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 19 2457-2466
DOI: 10.1093/hmg/ddg265
© 2003 Oxford University Press

Gene expression changes presage neurodegeneration in a Drosophila model of Parkinson's disease

Clemens R. Scherzer1, Roderick V. Jensen1,2, Steven R. Gullans1 and Mel B. Feany3,*

1Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Cambridge, MA 02319, USA, 2Department of Physics, Wesleyan University, Middletown, CT 06457, USA and 3Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA

Received May 6, 2003; Revised July 17, 2003; Accepted July 30, 2003

Transgenic Drosophila expressing human {alpha}-synuclein faithfully replicate essential features of human Parkinson's disease, including age-dependent loss of dopaminergic neurons, Lewy-body-like inclusions and locomotor impairment. To define the transcriptional program encoding molecular machinery involved in {alpha}-synuclein pathology, we characterized expression of the entire Drosophila genome at pre-symptomatic, early and advanced disease stages. Fifty-one signature transcripts, including lipid, energy and membrane transport mRNAs, were tightly associated with {alpha}-synuclein expression. Most importantly, at the pre-symptomatic stage, when the potential for neuroprotection is greatest, expression changes revealed specific pathology. In age-matched tau transgenic Drosophila, the transcription of {alpha}-synuclein associated genes was normal, suggesting highly distinct pathways of neurodegeneration. Temporal profiling of progressive gene expression changes in neurodegenerative disease models provides unbiased starting points for defining disease mechanisms and for identifying potential targets for neuroprotective drugs at pre-clinical stages.

* To whom correspondence should be addressed at: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Room 514, Boston, MA 02115, USA. Tel: +1 6172780008; Fax: +1 6177325795; Email: mel_feany{at}hms.harvard.edu


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