Ferroptosis-related factors in the substantia nigra are associated with Parkinson's disease.
Ferroptosis-related factors in the substantia nigra are associated with Parkinson's disease.
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DOI：
10.1038/s41598-023-42574-4
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发表时间：
2023-09-16
影响因子：
4.6
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中科院分区：
文献类型：
--
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铁凋亡是一种铁依赖性、脂质过氧化驱动的细胞死亡途径，而帕金森病（PD）患者在脑中表现出铁沉积和脂质过氧化。因此，铁下垂的特征与PD的病理生理学特征高度重叠。尽管存在这种表面联系，但尚未深入研究PD中黑质（SN）中多巴胺能神经元和/或胶质细胞中铁凋亡相关（Fr）蛋白的可能作用。为了探索PD患者中不同SN细胞类型与单细胞水平的铁凋亡之间的相关性，并探索可能影响多巴胺能神经元对铁凋亡敏感性的基因，我们对来自基因表达综合数据库（GEO）的单细胞RNA序列（RNA-seq）集（GSE 178265）进行了计算机分析。我们确定了差异表达基因（DEG）在不同类型的细胞在人类SN，并进行富集分析，构建一个蛋白质-蛋白质相互作用网络从多巴胺能神经元的DEG与Metascape数据库。我们检查了FerrDb数据库中存在的Fr基因与来自GSE 178265组的DEG的交叉，以鉴定不同脑细胞中的Fr-DEG。此外，我们鉴定了编码分泌蛋白的Fr-DEG，以暗示PD中铁凋亡的潜在刺激中的细胞-细胞相互作用。我们鉴定的Fr-DEG使用批量RNA-seq组（GSE 49036和GSE 20164）进行验证。PD患者黑质多巴胺能神经元数量减少。有趣的是，非多巴胺能神经元拥有最少的DEG。多巴胺能神经元DEGs的富集分析揭示了PD中跨化学突触传递和ATP代谢过程的变化。分泌的Fr-DEG鉴定为铜蓝蛋白（CP），高迁移率族蛋白1（HMGB 1）和转铁蛋白（TF）。来自GEO数据库的批量RNA-seq集证明CP表达在PD脑中增加。总之，我们的研究结果确定CP作为一个潜在的治疗目标，以保护多巴胺能神经元，减少神经元的敏感性，铁凋亡。
Ferroptosis is an iron-dependent, lipid peroxidation-driven cell death pathway, while Parkinson’s disease (PD) patients exhibit iron deposition and lipid peroxidation in the brain. Thus, the features of ferroptosis highly overlap with the pathophysiological features of PD. Despite this superficial connection, the possible role(s) of ferroptosis-related (Fr) proteins in dopaminergic neurons and/or glial cells in the substantia nigra (SN) in PD have not been examined in depth. To explore the correlations between the different SN cell types and ferroptosis at the single-cell level in PD patients, and to explore genes that may affect the sensitivity of dopaminergic neurons to ferroptosis, we performed in silico analysis of a single cell RNA sequence (RNA-seq) set (GSE178265) from the Gene Expression Omnibus (GEO) database. We identified differentially expressed genes (DEGs) in the different cell types in the human SN, and proceeded to perform enrichment analysis, constructing a protein–protein interaction network from the DEGs of dopaminergic neurons with the Metascape database. We examined the intersection of Fr genes present in the FerrDb database with DEGs from the GSE178265 set to identify Fr-DEGs in the different brain cells. Further, we identified Fr-DEGs encoding secreted proteins to implicate cell–cell interactions in the potential stimulation of ferroptosis in PD. The Fr-DEGs we identified were verified using the bulk RNA-seq sets (GSE49036 and GSE20164). The number of dopaminergic neurons decreased in the SN of PD patients. Interestingly, non-dopaminergic neurons possessed the fewest DEGs. Enrichment analysis of dopaminergic neurons’ DEGs revealed changes in transmission across chemical synapses and ATP metabolic process in PD. The secreted Fr-DEGs identified were ceruloplasmin (CP), high mobility group box 1 (HMGB1) and transferrin (TF). The bulk RNA-seq set from the GEO database demonstrates that CP expression is increased in the PD brain. In conclusion, our results identify CP as a potential therapeutic target to protect dopaminergic neurons by reducing neurons’ sensitivity to ferroptosis.
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影响因子：
25
作者：
Kamath, Tushar;Abdulraouf, Abdulraouf;Burris, S. J.;Langlieb, Jonah;Gazestani, Vahid;Nadaf, Naeem M.;Balderrama, Karol;Vanderburg, Charles;Macosko, Evan Z.
通讯作者：
Macosko, Evan Z.
影响因子：
9
作者：
Li, Zhong-Da;Li, Haiyan;Kang, Shaomeng;Cui, Yan-Ge;Zheng, Huiwen;Wang, Peina;Han, Kang;Yu, Peng;Chang, Yan-Zhong
通讯作者：
Chang, Yan-Zhong
影响因子：
5.7
作者：
Magna, Melinda;Pisetsky, David S.
通讯作者：
Pisetsky, David S.
DOI：
10.1073/pnas.92.7.2539
发表时间：
1995-03-28
影响因子：
11.1
作者：
HARRIS, ZL;TAKAHASHI, Y;GITLIN, JD
通讯作者：
GITLIN, JD
影响因子：
3.3
作者：
Loeffler, DA;Sima, AAF;LeWitt, PA
通讯作者：
LeWitt, PA