Single-nuclei RNA sequencing uncovers heterogenous transcriptional signatures in Parkinson's disease associated with nuclear receptor-related factor 1 defect.
Single-nuclei RNA sequencing uncovers heterogenous transcriptional signatures in Parkinson's disease associated with nuclear receptor-related factor 1 defect.
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DOI：
10.4103/1673-5374.366493
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发表时间：
2023-09
影响因子：
6.1
通讯作者：
Gao DS
中科院分区：
文献类型：
--
作者：
Kambey PA;Liu WY;Wu J;Bosco B;Nadeem I;Kanwore K;Gao DS
以往的研究发现，参与多巴胺能神经元发育、分化、存活和变性的核受体相关因子1（Nurr 1）的缺乏与帕金森病有关，但其作用机制尚不清楚。在这里，我们首先确定了敲除Nurr 1的反应，通过进行液相色谱串联质谱。我们发现231个基因在Nurr 1缺陷的多巴胺能神经元中高度表达，其中14个基因与基于京都基因和基因组百科全书分析的帕金森病通路有关。为了更好地理解Nurr 1缺陷如何自主地引起多巴胺能神经元的下降和帕金森病症状的缓解，我们在Nurr 1 LV-shRNA小鼠模型中进行了单核RNA测序。结果显示，黑质细胞的异质性和一些激活的基因，其中的优势编码的主要组织相容性II复合体的组件。Cd 74、H2-Ab 1、H2-Aa、H2-Eb 1、Lyz 2、Mrc 1、Slc 6a 3、Slc 47 a1、Ms 4a 4 b和Ptprc 2为前10位差异表达基因。免疫荧光染色显示，Nurr 1基因敲低后，小鼠脑组织中CD 74免疫反应阳性细胞的数量明显增加。此外，在用6-羟基多巴胺治疗诱导的帕金森病小鼠模型中，Cd 74表达增加。两者合计，我们的研究结果表明，Nurr 1缺陷导致Cd 74表达增加，从而导致多巴胺能神经元的破坏。这些发现为帕金森病的治疗提供了潜在的治疗靶点。
Previous studies have found that deficiency in nuclear receptor-related factor 1 (Nurr1), which participates in the development, differentiation, survival, and degeneration of dopaminergic neurons, is associated with Parkinson’s disease, but the mechanism of action is perplexing. Here, we first ascertained the repercussion of knocking down Nurr1 by performing liquid chromatography coupled with tandem mass spectrometry. We found that 231 genes were highly expressed in dopaminergic neurons with Nurr1 deficiency, 14 of which were linked to the Parkinson’s disease pathway based on Kyoto Encyclopedia of Genes and Genomes analysis. To better understand how Nurr1 deficiency autonomously invokes the decline of dopaminergic neurons and elicits Parkinson’s disease symptoms, we performed single-nuclei RNA sequencing in a Nurr1 LV-shRNA mouse model. The results revealed cellular heterogeneity in the substantia nigra and a number of activated genes, the preponderance of which encode components of the major histocompatibility II complex. Cd74, H2-Ab1, H2-Aa, H2-Eb1, Lyz2, Mrc1, Slc6a3, Slc47a1, Ms4a4b, and Ptprc2 were the top 10 differentially expressed genes. Immunofluorescence staining showed that, after Nurr1 knockdown, the number of CD74-immunoreactive cells in mouse brain tissue was markedly increased. In addition, Cd74 expression was increased in a mouse model of Parkinson’s disease induced by treatment with 6-hydroxydopamine. Taken together, our results suggest that Nurr1 deficiency results in an increase in Cd74 expression, thereby leading to the destruction of dopaminergic neurons. These findings provide a potential therapeutic target for the treatment of Parkinson’s disease.
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