Single-cell transcriptomics of human iPSC differentiation dynamics reveal a core molecular network of Parkinson's disease.
Single-cell transcriptomics of human iPSC differentiation dynamics reveal a core molecular network of Parkinson's disease.
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DOI：
10.1038/s42003-021-02973-7
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发表时间：
2022-01-13
影响因子：
5.9
通讯作者：
Skupin A
中科院分区：
文献类型：
--
作者：
Novak G;Kyriakis D;Grzyb K;Bernini M;Rodius S;Dittmar G;Finkbeiner S;Skupin A
帕金森病(PD)是第二常见的神经退行性疾病，其特征是中脑多巴胺能神经元(MDA)的丢失。其潜在机制仅有部分了解，目前尚无逆转帕金森病进展的治疗方法。在这里，我们使用从携带PINK1基因ILE368ASN突变的人诱导多能干细胞(HiPSCs)分化的丙二醛神经元来研究疾病机制，PINK1基因与帕金森病密切相关。单细胞RNA测序(RNAseq)和PINK1-ILE368ASN和对照细胞系的基因表达分析发现了在MDA神经元分化过程中差异表达的基因。网络分析显示，这些基因形成了一个核心网络，其成员与所有已知的19个编码帕金森氏病相关蛋白的基因相互作用。这个核心网络包括与PD相关的关键通路，包括泛素化、线粒体功能、蛋白质处理、RNA代谢和囊泡运输。蛋白质组学分析显示，PINK1-ILE368ASN神经元的多巴胺代谢蛋白发生了一致的变化，表明PINK1-ILE368ASN神经元存在多巴胺能代谢缺陷。我们的发现表明，存在一个与帕金森病病理相关的通路汇聚的网络，并对帕金森病的表型异质性提供了包容的解释。Gabriela Novak等人。利用scRNA-seq研究帕金森氏病患者或健康对照组IPSC来源的中脑多巴胺能神经元的表达谱。他们的研究结果表明了一个与帕金森氏病病理相关的核心分子网络，并为这一危重疾病的研究提供了未来的资源。
Parkinson’s disease (PD) is the second-most prevalent neurodegenerative disorder, characterized by the loss of dopaminergic neurons (mDA) in the midbrain. The underlying mechanisms are only partly understood and there is no treatment to reverse PD progression. Here, we investigated the disease mechanism using mDA neurons differentiated from human induced pluripotent stem cells (hiPSCs) carrying the ILE368ASN mutation within the PINK1 gene, which is strongly associated with PD. Single-cell RNA sequencing (RNAseq) and gene expression analysis of a PINK1-ILE368ASN and a control cell line identified genes differentially expressed during mDA neuron differentiation. Network analysis revealed that these genes form a core network, members of which interact with all known 19 protein-coding Parkinson’s disease-associated genes. This core network encompasses key PD-associated pathways, including ubiquitination, mitochondrial function, protein processing, RNA metabolism, and vesicular transport. Proteomics analysis showed a consistent alteration in proteins of dopamine metabolism, indicating a defect of dopaminergic metabolism in PINK1-ILE368ASN neurons. Our findings suggest the existence of a network onto which pathways associated with PD pathology converge, and offers an inclusive interpretation of the phenotypic heterogeneity of PD. Gabriela Novak et al. utilize scRNA-seq to investigate expression profiles in iPSC-derived midbrain dopaminergic neurons from Parkinson’s disease patients or healthy controls. Their results suggest a core molecular network associated with Parkinson’s disease pathology, and provide a future resource for investigation of this critical disorder.
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影响因子：
15.1
作者：
Ando M;Fiesel FC;Hudec R;Caulfield TR;Ogaki K;Górka-Skoczylas P;Koziorowski D;Friedman A;Chen L;Dawson VL;Dawson TM;Bu G;Ross OA;Wszolek ZK;Springer W
通讯作者：
Springer W
影响因子：
14.9
作者：
Finger JH;Smith CM;Hayamizu TF;McCright IJ;Eppig JT;Kadin JA;Richardson JE;Ringwald M
通讯作者：
Ringwald M
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
DOI：
10.1038/nsb1101-963
发表时间：
2001-11-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Burkhard, P;Dominici, P;Malashkevich, VN
通讯作者：
Malashkevich, VN
影响因子：
6.2
作者：
Bonilla, Sonia;Hall, Anita C.;Arenas, Ernest
通讯作者：
Arenas, Ernest