Transcriptome profiling of 6-OHDA model of Parkinson’s disease

Abstract

Analysis of monogenic forms and candidate genes of Parkinson’s disease (PD) does not allow to describe completely the contribution of genetic factors to the etiopathogenesis of the disorder. An approach associated with an analysis of changes in a transcriptome pattern during the development of the disease in model objects can be used to identify new candidate genes that are involved in the pathogenesis of PD. In this work, we performed a transcriptome analysis of a PD model, created via stereotaxic unilateral introduction of the 6-hydroxidopamine (6-OHDA) into the substantia nigra pars compacta (SNpc) of a rat brain, to identify new candidate genes for PD. We studied transcriptome alterations in the substantia nigra of the rat brains 2 weeks after toxin administration, when the rats developed the Parkinson-like phenotype, and 4 weeks after toxin administration, when maximal changes in the behavior of animals were observed. The transcriptome analysis of the substantia nigra of the rat brains at the first time point (2 weeks) revealed changes in expression of genes that were clustered with high significance (p < 0.01, modified Fisher extract p value) into three metabolic pathways according to protein participation: modification of the extracellular matrix, signal transduction (including genes encoding signal peptides), and inflammation processes. This likely indicates that, during this time nonspecific effects associated with the response to surgery took place in the substantia nigra of the rats. Concomitantly, the situation changed dramatically and a response associated with damage to the nervous tissue was observed 4 weeks after neurotoxin administration. As a result, we identified five metabolic pathways containing predominantly genes, that encode protein products that are involved in the processes of neuron projection, normal functioning of the soma and dendrites of neurons, synaptic transmission, and transmission of nerve impulses (p < 0.01, modified Fisher extract p value).