Components of the endocannabinoid and dopamine systems are dysregulated in Huntington's disease: analysis of publicly available microarray datasets

Abstract

The endocannabinoid system (ECS) and the dopaminergic system (DAS) are two major regulators of basal ganglia function. During Huntington's disease (HD) pathogenesis, the expression of genes in both the ECS and DAS is dysregulated. The purpose of this study was to determine the changes that were consistently observed in the ECS and DAS during HD progression in the central nervous system (CNS) and in the periphery in different models of HD and human HD tissue. To do this, we conducted a meta-analysis of differential gene expression in the ECS and DAS using publicly available microarray data. The consolidated data were summarized as observed changes in gene expression (OCGE) using a weighted sum for each gene. In addition, consolidated data were compared to previously published studies that were not available in the gene expression omnibus (GEO) database. The resulting data confirm gene expression changes observed using different approaches and provide novel insights into the consistency between changes observed in human tissue and various models, as well as disease stage- and tissue-specific transcriptional dysregulation in HD. The major implication of the systems-wide data presented here is that therapeutic strategies targeting the ECS or DAS must consider the dynamic changes in gene expression over time and in different body areas, which occur during HD progression and the interconnectedness of the two systems.

Keywords: Bioinformatics; Huntington's disease; cannabinoid; dopamine; meta-analysis; microarray.

Figure 1

Transcriptional dysregulation of the ECS in microarray studies of HD. (A, B) Data are represented as the OCGE, which was the sum of the scoring matrix for each gene divided by the number of reports used in to generate that score ± the sum of the scoring matrix for all studies that did not report a change in the expression of each gene. Open boxes denote an OCGE different from 0 (P < 0.05). (A) Overall changes in gene expression in the CNS. (B) Overall changes in gene expression in the periphery. C–E) Significant OCGE relative to 0 are indicated by color. White: no change; yellow: decreased; light blue: increased. (C) Changes in gene expression in the CNS described according to disease stage. (D) Changes in gene expression in the periphery described according to disease stage. (E) Changes in gene expression in the CNS described according to model.

Figure 2

Transcriptional dysregulation of the DAS in microarray studies of HD. (A, B) Data are represented as the OCGE, which was the sum of the scoring matrix for each gene divided by the number of reports used in to generate that score ± the sum of the scoring matrix for all studies that did not report a change in the expression of each gene. Open boxes denote a OCGE different from 0 (P < 0.05). (A) Overall changes in gene expression in the CNS. (B) Overall changes in gene expression in the periphery. C, D) Significant OCGEs relative to 0 are indicated by color. White: no change; yellow: decreased; light blue: increased. (C) Changes in gene expression in the CNS described according to disease stage. (D) Changes in gene expression in the periphery described according to disease stage.