Modulation of miR-181 influences dopaminergic neuronal degeneration in a mouse model of Parkinson's disease.
Modulation of miR-181 influences dopaminergic neuronal degeneration in a mouse model of Parkinson's disease.
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DOI：
10.1016/j.omtn.2022.02.007
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发表时间：
2022-06-14
期刊：
影响因子：
--
通讯作者：
Boudreau RL
中科院分区：
文献类型：
--
作者：
Stein CS;McLendon JM;Witmer NH;Boudreau RL
帕金森病（PD）是由黑质（SN）中多巴胺（DA）能神经元的缺失引起的。虽然PD的发病机制尚未完全了解，但研究涉及基因调控，线粒体功能和神经元活性的扰动。microRNA（miRs）是抑制靶mRNA的不同子集的小基因调控RNA，并且一些研究已经注意到PD脑中的miR表达改变。例如，miR-181 a在脑中丰富，并且在PD患者脑样品中增加;然而，这与疾病的相关性仍不清楚。在这里，我们发现miR-181靶mRNA在衰老和PD大脑中广泛下调。为了解决miR-181家族是否在PD发病机制中发挥作用，我们产生了腺相关病毒（AAV）来过表达和抑制miR-181亚型。在与过表达α-突触核蛋白（aSyn）的AAV共注射到小鼠SN（PD模型）中后，我们发现适度的miR-181 a/B过表达加剧了aSyn诱导的DA神经元损失，而miR-181抑制相对于对照（单独的GFP和/或乱序RNA）具有神经保护作用。此外，单独在SN中延长的miR-181过表达引起可测量的神经毒性，这与增加的免疫应答一致。mRNA-seq分析显示，miR-181 a/B抑制参与突触传递、神经突生长和线粒体呼吸的基因，沿着几个在PD中具有已知保护作用和遗传联系的基因。Stein等人发现miR-181靶基因在衰老和帕金森病（PD）大脑中的表达广泛降低。在小鼠研究中，miR-181上调导致多巴胺神经元变性，并加剧了α-突触核蛋白（aSyn）过表达引起的神经元丢失，而miR-181抑制可保护免受aSyn诱导的毒性。
Parkinson's disease (PD) is caused by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Although PD pathogenesis is not fully understood, studies implicate perturbations in gene regulation, mitochondrial function, and neuronal activity. MicroRNAs (miRs) are small gene regulatory RNAs that inhibit diverse subsets of target mRNAs, and several studies have noted miR expression alterations in PD brains. For example, miR-181a is abundant in the brain and is increased in PD patient brain samples; however, the disease relevance of this remains unclear. Here, we show that miR-181 target mRNAs are broadly downregulated in aging and PD brains. To address whether the miR-181 family plays a role in PD pathogenesis, we generated adeno-associated viruses (AAVs) to overexpress and inhibit the miR-181 isoforms. After co-injection with AAV overexpressing alpha-synuclein (aSyn) into mouse SN (PD model), we found that moderate miR-181a/b overexpression exacerbated aSyn-induced DA neuronal loss, whereas miR-181 inhibition was neuroprotective relative to controls (GFP alone and/or scrambled RNA). Also, prolonged miR-181 overexpression in SN alone elicited measurable neurotoxicity that is coincident with an increased immune response. mRNA-seq analyses revealed that miR-181a/b inhibits genes involved in synaptic transmission, neurite outgrowth, and mitochondrial respiration, along with several genes having known protective roles and genetic links in PD. Stein et al. find a broadly decreased expression of miR-181 target genes in aging and Parkinson’s disease (PD) brains. In studies in mice, miR-181 upregulation caused the degeneration of dopamine neurons and exacerbated neuronal loss elicited by alpha-synuclein (aSyn) overexpression, whereas miR-181 inhibition protected against aSyn-induced toxicity.
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