Analysis of Gene Expression in Parkinson's Disease: Possible Involvement of Neurotrophic Support and Axon Guidance in Dopaminergic Cell Death

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. We have studied alterations in gene expression in the substantia nigra, the caudate nucleus and putamen of four PD patients and four matched controls using custom designed Agilent microarrays. To gain insight into changes in gene expression during early stages of dopaminergic neurodegeneration, we selectively investigated the relatively spared parts of the PD substantia nigra, and correlated gene expression changes with alterations in neuronal density. We identified changes in the expression of 287 transcripts in the substantia nigra, 16 transcripts in the caudate nucleus and four transcripts in the putamen. For selected transcripts, transcriptional alterations were confirmed with qPCR on a larger set of seven PD cases and seven matched controls. We detected concerted changes in functionally connected groups of genes. In the PD substantia nigra, we observed strong evidence for a reduction in neurotrophic support and alterations in axon guidance cues. As the changes occur in relatively spared parts of the PD substantia nigra, they suggest novel disease mechanisms involving neurotrophic support and axon guidance in early stages of cellular stress events, ultimately leading to dopaminergic cell death in PD.