Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulated in Exercise in a Mouse Model of Parkinson’s Disease

Abstract

BackgroundExercise plays an essential role in improving motor symptoms in Parkinson’s disease (PD), but the underlying mechanism in the central nervous system remains unclear.MethodsMotor ability was observed after 12-week treadmill exercise on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. RNA-sequencing on four brain regions (cerebellum, cortex, substantia nigra (SN), and striatum) from control animals, MPTP-induced PD, and MPTP-induced PD model treated with exercise for 12 weeks were performed. Transcriptional networks on the four regions were further identified by an integrative network biology approach.ResultsThe 12-week treadmill exercise significantly improved the motor ability of an MPTP-induced mouse model of PD. RNA-seq analysis showed SN and striatum were remarkably different among individual region’s response to exercise in the PD model. Especially, synaptic regulation pathways about axon guidance, synapse assembly, neurogenesis, synaptogenesis, transmitter transport-related pathway, and synaptic regulation genes, including Neurod2, Rtn4rl2, and Cd5, were upregulated in SN and striatum. Lastly, immunofluorescence staining revealed that exercise rescued the loss of TH+ synapses in the striatal region in PD mice, which validates the key role of synaptic regulation pathways in exercise-induced protective effects in vivo.ConclusionSN and striatum are important brain regions in which critical transcriptional changes, such as in synaptic regulation pathways, occur after the exercise intervention on the PD model.

Publicly available ex vivo transcriptomics datasets to explore CNS physiology and neurodegeneration: state of the art and perspectives

“…Further, it was characterized by dysregulation in transcripts involved in B cell and T cell signaling, suggesting the involvement of adaptive immunity in this disorder ( Dijkstra et al, 2015 ; Table 1 , GSE49036). Transcriptional changes after exercise were described in substantia nigra (SN) and striatum in the MPTP-induced PD model ( Tong et al, 2022 ; Table 1 , GSE205907). Brain RNA-seq highlighted dysregulation of ribosomal genes and led to the definition of stress granule formation in a mouse model for C9orf72 ALS ( Table 1 , GSE112931).…”

Genes critical for development and differentiation of dopaminergic neurons are downregulated in Parkinson’s disease

“…More recently approaches using RNA sequencing (RNA-seq) offer good alternative to examine global gene expression changes in disease state. Several PD studies have employed the RNA-seq technique to understand gene expression changes in the MPTP mouse model (Yang et al 2021;Tong et al 2022;Guo et al 2022), patient brain regions (Keo et al 2020;Aguila et al 2021;Tiklová et al 2021), blood from PD patients (Soreq et al 2015;Infante et al 2016;Moni et al 2019), and iPSCs derived from PD patients (Booth et al 2019;van den Hurk et al 2022).…”