Navarro Elisa, Efthymiou Anastasia G, Parks Madison, Riboldi Giulietta M, Vialle Ricardo A, Udine Evan, Muller Benjamin Z, Humphrey Jack, Allan Amanda, Argyrou Charlie Charalambos, Lopes Katia de Paiva, Münch Alexandra, Raymond Deborah, Sachdev Rivka, Shanker Vicki L, Miravite Joan, Katsnelson Viktoryia, Leaver Katherine, Frucht Steve, Bressman Susan B, Marcora Edoardo, Saunders-Pullman Rachel, Goate Alison, Raj Towfique
Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
bioRxiv. 2024 May 31:2024.05.27.594821. doi: 10.1101/2024.05.27.594821.
The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is a major risk factor for the development of Parkinson's disease (PD). LRRK2, although ubiquitously expressed, is highly abundant in cells of the innate immune system. Given the importance of central and peripheral immune cells in the development of PD, we sought to investigate the consequences of the G2019S mutation on microglial and monocyte transcriptome and function. We have generated large-scale transcriptomic profiles of isogenic human induced microglial cells (iMGLs) and patient derived monocytes carrying the G2019S mutation under baseline culture conditions and following exposure to the proinflammatory factors IFNγ and LPS. We demonstrate that the G2019S mutation exerts a profound impact on the transcriptomic profile of these myeloid cells, and describe corresponding functional differences in iMGLs. The G2019S mutation led to an upregulation in lipid metabolism and phagolysosomal pathway genes in untreated and LPS/IFNγ stimulated iMGLs, which was accompanied by an increased phagocytic capacity of myelin debris. We also identified dysregulation of cell cycle genes, with a downregulation of the E2F4 regulon. Transcriptomic characterization of human-derived monocytes carrying the G2019S mutation confirmed alteration in lipid metabolism associated genes. Altogether, these findings reveal the influence of G2019S on the dysregulation of the myeloid cell transcriptome under proinflammatory conditions.
富含亮氨酸重复激酶2（LRRK2）基因中的G2019S突变是帕金森病（PD）发生的主要危险因素。LRRK2虽然在全身广泛表达，但在固有免疫系统细胞中高度丰富。鉴于中枢和外周免疫细胞在PD发生中的重要性，我们试图研究G2019S突变对小胶质细胞和单核细胞转录组及功能的影响。我们已经生成了携带G2019S突变的同基因人诱导小胶质细胞（iMGLs）和患者来源单核细胞在基线培养条件下以及暴露于促炎因子IFNγ和LPS后的大规模转录组图谱。我们证明G2019S突变对这些髓样细胞的转录组图谱产生了深远影响，并描述了iMGLs中相应的功能差异。G2019S突变导致未处理和LPS/IFNγ刺激的iMGLs中脂质代谢和吞噬溶酶体途径基因上调，同时伴有髓鞘碎片吞噬能力增强。我们还发现细胞周期基因失调，E2F4调控子下调。对携带G2019S突变的人源单核细胞进行转录组特征分析证实了脂质代谢相关基因的改变。总之，这些发现揭示了G2019S在促炎条件下对髓样细胞转录组失调的影响。
