Dysregulation of Gene Expression in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioined Mouse Substantia Nigra. Mus musculus

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. Keywords: Parkinson's disease; MPTP; gene expression; microarray; cytoskeleton; mouse Overall design: The demonstration of a shared pathogenic cascade among the differently triggered forms of PD requires a characterization of the molecular changes accompanying the temporal evolution of midbrain dopamine injury, dysfunction, and cell death. Identification of consensus molecular responses is aided by the application of robust exploratory methods that permit cataloging of changes in gene expression. Here, mRNA profiling by two leading oligonucleotide array systems, Affymetrix GeneChips and Amersham CodeLink, was used to reveal candidate molecules that are dysregulated during MPP+-induced injury of the mouse SN in a chronic MPTP model of PD. Different time points were examined to discriminate temporal patterns of gene expression in this model. Applying three separate data mining methods, we found consistent downregulation of genes encoding proteins functioning in the maintenance of the cytoskeleton, neurotransmitter release, and trophic signaling in the SN. Additionally, decline in cell cycle regulatory genes is suggestive of abortive mitosis and death of postmitotic neurons.