Effects of Age and MPTP-Induced Parkinson's Disease on the Expression of Genes Associated with the Regulation of the Sleep-Wake Cycle in Mice

Abstract

Parkinson's disease (PD) is characterized by a long prodromal period, during which patients often have sleep disturbances. The histaminergic system and circadian rhythms play an important role in the regulation of the sleep-wake cycle. Changes in the functioning of these systems may be involved in the pathogenesis of early stages of PD and may be age-dependent. Here, we have analyzed changes in the expression of genes associated with the regulation of the sleep-wake cycle (Hnmt, Hrh1, Hrh3, Per1, Per2, and Chrm3) in the substantia nigra (SN) and striatum of normal male mice of different ages, as well as in young and adult male mice with an MPTP-induced model of the early symptomatic stage (ESS) of PD. Age-dependent expression analysis in normal mouse brain tissue revealed changes in Hrh3, Per1, Per2, and Chrm3 genes in adult mice relative to young mice. When gene expression was examined in mice with the MPTP-induced model of the ESS of PD, changes in the expression of all studied genes were found only in the SN of adult mice with the ESS model of PD. These data suggest that age is a significant factor influencing changes in the expression of genes associated with sleep-wake cycle regulation in the development of PD.

Keywords: MPTP model; Parkinson’s disease; circadian genes; gene expression; histamine; neurodegeneration; sleep–wake cycle; transcriptome.

Figure 1

Results of analysis of changes in expression of genes associated with regulation of the sleep–wake cycle in the striatum and SN of adult mice (6 months old) relative to young mice (5–6 weeks old) presented as bar plots showing the individual data points. Abbreviations: str—striatum; SN—substantia nigra; NaCl—control mice. * p < 0.05, ** p < 0.01.

Figure 2

Results of analysis of changes in expression of genes associated with regulation of the sleep–wake cycle in the striatum and SN of mice with MPTP-induced model of the ESS of PD presented as bar plots showing the individual data points. Abbreviations: str—striatum; SN—substantia nigra; NaCl—control mice; MPTP—mice with MPTP-induced model of the ESS of PD. * p < 0.05, ** p < 0.01.

Figure 3

Interaction network of the studied genes. The network was constructed using Pathway Studio v. 12.4.0.5.

Figure 4

Schematic showing the possible impact of changes in the expression of the genes associated with regulation of the sleep–wake cycle during aging. Solid lines indicate interactions confirmed in the literature. Dotted lines indicate possible interactions. Up arrows (↑) indicate an increase, down arrows (↓) indicate a decrease. Abbreviation: HA—histamine.

Figure 5

Schematic showing the possible impact of changes in the expression of the genes associated with regulation of the sleep–wake cycle on the ESS of PD in adult mice. Sharp arrows (→) indicate stimulation, blunt arrows (┴) indicate inhibition, up arrows (↑) indicate an increase, down arrows (↓) indicate a decrease Abbreviations: HA—histamine; REM—rapid eye movement.