Transcriptomic approach predicts a major role for transforming growth factor beta type 1 pathway in L-Dopa-induced dyskinesia in parkinsonian rats.
Transcriptomic approach predicts a major role for transforming growth factor beta type 1 pathway in L-Dopa-induced dyskinesia in parkinsonian rats.
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DOI：
10.1111/gbb.12690
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Papa SM
中科院分区：
文献类型：
--
作者：
Dyavar SR;Potts LF;Beck G;Dyavar Shetty BL;Lawson B;Podany AT;Fletcher CV;Amara RR;Papa SM
帕金森病患者长期左旋多巴（LID）治疗引起的运动障碍与纹状体功能改变有关，其分子基础尚不清楚。在这里，转录组学的方法被应用于全面分析纹状体组织中的独特调控基因，其特定的途径，以及在啮齿动物模型LID的功能和疾病相关的网络。该方法已将转化生长因子β 1（TGFβ1）确定为运动障碍动物中高度上调的基因。根据差异表达基因（> 1.5倍变化和P < 0.05），TGFβ1通路是LID发生后纹状体中最高的异常调节通路。TGFβ1通路特异性基因TGFβ1、INHBA、AMHR 2和PMEPA 1的诱导也与NPTX 2、PDP 1、SCG 2、SYNPR、TAC 1、TH、TNNT 1基因的调节有关。转录网络和上游调节因子分析已经确定了以AKT为中心的功能和以ERK为中心的疾病网络，揭示了TGFβ1、IL-1β和TNFα与LID发展的相关性。因此，结果支持TGFβ1通路是LID的致病机制的主要贡献者。
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.
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影响因子：
4.3
作者：
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通讯作者：
Veiga-Fernandes H