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The Journal of Neuroscience, August 25, 2004, 24(34):7445-7454; doi:10.1523/JNEUROSCI.4204-03.2004

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Neurobiology of Disease
Dysregulation of Gene Expression in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Mouse Substantia Nigra

Renee M. Miller,^1 * Linda M. Callahan,^1,3 * Cindy Casaceli,¹ Linlin Chen,¹ Gretchen L. Kiser,² Buena Chui,² Tamma M. Kaysser-Kranich,² Timothy J. Sendera,² Chockalingam Palaniappan,² and Howard J. Federoff¹

¹Center for Aging and Developmental Biology, Aab Institute of Biomedical Sciences, University of Rochester, Rochester, New York 14642, ²GE Healthcare (formerly Amersham Biosciences), Chandler, Arizona 85248, and ³Department of Pathology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Parkinson's disease pathogenesis proceeds through several phases, culminating in the loss of dopaminergic neurons of the substantia nigra (SN). Although the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of oxidative SN injury is frequently used to study degeneration of dopaminergic neurons in mice and non-human primates, an understanding of the temporal sequence of molecular events from inhibition of mitochondrial complex 1 to neuronal cell death is limited. Here, microarray analysis and integrative data mining were used to uncover pathways implicated in the progression of changes in dopaminergic neurons after MPTP administration. This approach enabled the identification of small, yet consistently significant, changes in gene expression within the SN of MPTP-treated animals. Such an analysis disclosed dysregulation of genes in three main areas related to neuronal function: cytoskeletal stability and maintenance, synaptic integrity, and cell cycle and apoptosis. The discovery and validation of these alterations provide molecular evidence for an evolving cascade of injury, dysfunction, and cell death.

Key words: Parkinson's disease; MPTP; gene expression; microarray; cytoskeleton; mouse

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Received Sep 12, 2003; revised July 11, 2004; accepted July 13, 2004.

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