Transcriptomic approach predicts a major role for transforming growth factor beta type 1 pathway in L‐Dopa‐induced dyskinesia in parkinsonian rats

Abstract

Dyskinesia induced by long‐term L‐Dopa (LID) therapy in Parkinson disease is associated with altered striatal function whose molecular bases remain unclear. Here, a transcriptomic approach was applied for comprehensive analysis of distinctively regulated genes in striatal tissue, their specific pathways, and functional‐ and disease‐associated networks in a rodent model of LID. This approach has identified transforming growth factor beta type 1 (TGFβ1) as a highly upregulated gene in dyskinetic animals. TGFβ1 pathway is a top aberrantly regulated pathway in the striatum following LID development based on differentially expressed genes (> 1.5 fold change and P < 0.05). The induction of TGFβ1 pathway specific genes, TGFβ1, INHBA, AMHR2 and PMEPA1 was also associated with regulation of NPTX2, PDP1, SCG2, SYNPR, TAC1, TH, TNNT1 genes. Transcriptional network and upstream regulator analyses have identified AKT‐centered functional and ERK‐centered disease networks revealing the association of TGFβ1, IL‐1β and TNFα with LID development. Therefore, results support that TGFβ1 pathway is a major contributor to the pathogenic mechanisms of LID.

Critical Role of Zinc Transporter (ZIP8) in Myeloid Innate Immune Cell Function and the Host Response against Bacterial Pneumonia

“…Ingenuity Pathway Analysis (IPA) software (Qiagen) was used to perform pathway enrichment, gene network, and upstream regulator analyses (URA) according to the standard protocols as previously described (39,40). A list of differentially expressed genes in a dataset with a minimum of 1.5-fold change and p value of <0.05 significance were compared between the two groups and uploaded into IPA.…”

Differential activation states of direct pathway striatal output neurons associated with the development of L-DOPA-induced dyskinesia

“…As observed previously, IEGs were upregulated by acute L-DOPA treatment ( Fos, Fosb, Junb, etc.). Other genes commonly associated with LID were also detected, including Pdyn, Arc, and Cytb (Dyavar et al, 2020; Smith et al, 2016; Sodersten et al, 2014). Glial– and oligodendrocyte-associated genes, such as Cx3cr1, Ptn, and Mbp , were further upregulated by acute L-DOPA treatment consistent with their increased cellular proportions following L-DOPA exposure.…”

“…Although bulk RNA-seq techniques have identified numerous changes in gene expression following LID development (Dyavar et al, 2020; Smith et al, 2016; Sodersten et al, 2014), due to the cellular complexity of the striatum (Gokce et al, 2016; Martin et al, 2019; Stanley et al, 2020), the particular cells specifically involved remain unknown. Recent advancements in single-nuclei (sn) RNA-seq technologies have facilitated the exploration of complex tissues with significant cellular heterogeneity, enabling the generation of cell type-specific transcriptional profiles during disease modeling and drug exposure.…”

Long non-coding RNA myocardial infarction-associated transcript promotes 1-Methyl-4-phenylpyridinium ion-induced neuronal inflammation and oxidative stress in Parkinson’s disease through regulating microRNA-221-3p/ transforming growth factor /nuclear factor E2-related factor 2 axis

“…It was reported that increased inflammatory response was implicated in neurodegenerative disorders, including Alzheimer’s disease, PD and amyotrophic lateral sclerosis, and a meta-analysis demonstrated that the expression of IL-1β, IL-6, and TGF-β were upregulated in PD [ 45 ]. Transcriptional network and upstream regulatory factor analysis indicated that TGFβ1 pathway was essential to the pathogenic mechanism of long-term L-Dopa therapy caused dyskinesia in PD patients [ 16 ]. There was evidence supporting that TGFβ1 was a key factor involved in the activation of microglia, which led to PD [ 46 ].…”

“…Previous evidences supported that neuroinflammatory processes were essential during the development of PD, and inflammatory cytokines in cerebrospinal fluid might be potential biomarkers for diagnosing PD [ 14 ]. It was reported that TGFβ1 and TGFβ2 levels were increased in ventricular cerebrospinal fluid of PD [ 15 ], while upregulation of TGFβ1 was associated with dyskinesia caused by long-term L-dopa therapy [ 16 ]. In addition, Nrf2 is a redox-sensitive transcription factor in the cytoplasm that facilitates cells to adapt to oxidative stress and inflammation [ 17 ].…”