PPP2R5D中的一个新发缺义突变改变了多巴胺通路和iPSC衍生中脑神经元的形态。

IF 4 2区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY STEM CELLS Pub Date : 2024-10-26 DOI:10.1093/stmcls/sxae068
Jasmine L Carter, Julian A N M Halmai, Jennifer J Waldo, Paula A Vij, Maribel Anguiano, Isaac J Villegas, Yu Xin Du, Jan Nolta, Kyle D Fink
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引用次数: 0

摘要

神经发育障碍(NDDs)的诱导多能干细胞(iPSC)模型通过揭示导致疾病病理的潜在分子和细胞机制,促进了对患者群体内部或不同患者群体之间共性和差异的理解。在这里,我们重点开发了一个与 PPP2R5D 相关的 NDD 人类模型,即约旦综合征,它与早发性帕金森病(EOPD)有关。在这里,我们试图了解多种细胞状态和神经元亚型的潜在分子和细胞表型,以深入了解乔丹综合征的病理。我们的工作发现,来自乔丹综合征患者的 iPSC 衍生中脑神经元在多巴胺相关通路和神经元结构方面存在显著差异。然后,我们评估了一种基于CRISPR的方法,用于在转录本水平上编辑患者神经干细胞中的杂合显性G-to-A突变。我们的研究结果表明,定点定向 RNA 编辑受 sgRNA 长度和细胞类型的影响。这些研究支持CRISPR RNA编辑系统选择性编辑神经干细胞中携带G-to-A突变的突变转录本的潜力,同时为NDDs患者提供了另一种编辑技术。
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A de novo Missense Mutation in PPP2R5D Alters Dopamine Pathways and Morphology of iPSC-derived Midbrain Neurons.

Induced pluripotent stem cell (iPSC) models of neurodevelopmental disorders (NDDs) have promoted an understanding of commonalities and differences within or across patient populations by revealing the underlying molecular and cellular mechanisms contributing to disease pathology. Here, we focus on developing a human model for PPP2R5D-related NDD, called Jordan syndrome, which has been linked to Early-Onset Parkinson's Disease (EOPD). Here we sought to understand the underlying molecular and cellular phenotypes across multiple cell states and neuronal subtypes in order to gain insight into Jordan syndrome pathology. Our work revealed that iPSC-derived midbrain neurons from Jordan syndrome patients display significant differences in dopamine-associated pathways and neuronal architecture. We then evaluated a CRISPR-based approach for editing heterozygous dominant G-to-A mutations at the transcript level in patient-derived neural stem cells. Our findings show site-directed RNA editing is influenced by sgRNA length and cell type. These studies support the potential for a CRISPR RNA editor system to selectively edit mutant transcripts harboring G-to-A mutations in neural stem cells while providing an alternative editing technology for those suffering from NDDs.

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来源期刊
STEM CELLS
STEM CELLS 医学-生物工程与应用微生物
CiteScore
10.30
自引率
1.90%
发文量
104
审稿时长
3 months
期刊介绍: STEM CELLS, a peer reviewed journal published monthly, provides a forum for prompt publication of original investigative papers and concise reviews. STEM CELLS is read and written by clinical and basic scientists whose expertise encompasses the rapidly expanding fields of stem and progenitor cell biology. STEM CELLS covers: Cancer Stem Cells, Embryonic Stem Cells/Induced Pluripotent Stem (iPS) Cells, Regenerative Medicine, Stem Cell Technology: Epigenetics, Genomics, Proteomics, and Metabonomics, Tissue-Specific Stem Cells, Translational and Clinical Research.
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