Department of Neurology, University of Virginia, Charlottesville, VA, USA; University of Virginia Stem Cell Core, Office of Research Core Administration, University of Virginia, Charlottesville, VA, USA; Department of Cell Biology, University of Virginia, Charlottesville, VA, USA.
Department of Biology, University of Virginia, Charlottesville, VA, USA.
Neurobiol Aging. 2020 Jun;90:125-134. doi: 10.1016/j.neurobiolaging.2020.02.011. Epub 2020 Feb 19.
A hexanucleotide repeat expansion on chromosome 9 open reading frame 72 (C9orf72) is associated with familial amyotrophic lateral sclerosis (ALS) and a subpopulation of patients with sporadic ALS and frontotemporal dementia. We used inducible pluripotent stem cells from neurotypic and C9orf72+ (C9+) ALS patients to derive neuronal progenitor cells. We demonstrated that C9+ and neurotypic neuronal progenitor cells differentiate into neurons. The C9+ neurons, however, spontaneously re-expressed cyclin D1 after 12 weeks, suggesting cell cycle re-engagement. Gene profiling revealed significant increases in senescence-associated genes in C9+ neurons. Moreover, C9+ neurons expressed high levels of mRNA for CXCL8, a chemokine overexpressed by senescent cells, while media from C9+ neurons contained significant levels of CXCL8, CXCL1, IL13, IP10, CX3CL1, and reactive oxygen species, which are components of the senescence-associated secretory phenotype. Thus, re-engagement of cell cycle-associated proteins and a senescence-associated secretory phenotype could be fundamental components of neuronal dysfunction in ALS and frontotemporal dementia.
9 号染色体开放阅读框 72（C9orf72）上的六核苷酸重复扩展与家族性肌萎缩侧索硬化症（ALS）以及一部分散发性 ALS 和额颞叶痴呆患者相关。我们使用诱导多能干细胞，源自神经型和 C9orf72+（C9+）ALS 患者，以获得神经元祖细胞。我们证明 C9+和神经型神经元祖细胞可分化为神经元。然而，C9+神经元在 12 周后自发重新表达细胞周期蛋白 D1，表明细胞周期重新激活。基因谱分析显示 C9+神经元中衰老相关基因显著增加。此外，C9+神经元表达高水平的 CXCL8 mRNA，这是衰老细胞过度表达的趋化因子，而 C9+神经元的培养基中含有大量的 CXCL8、CXCL1、IL13、IP10、CX3CL1 和活性氧，这些都是衰老相关分泌表型的组成部分。因此，细胞周期相关蛋白的重新激活和衰老相关分泌表型可能是 ALS 和额颞叶痴呆神经元功能障碍的基本组成部分。
