SNCA 基因座的倍增会加剧神经元核的衰老。
Multiplication of the SNCA locus exacerbates neuronal nuclear aging.
机构信息
Department of Neurology, Duke University Medical Center, Durham, NC, USA.
Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, USA.
出版信息
Hum Mol Genet. 2019 Feb 1;28(3):407-421. doi: 10.1093/hmg/ddy355.
Human-induced Pluripotent Stem Cell (hiPSC)-derived models have advanced the study of neurodegenerative diseases, including Parkinson's disease (PD). While age is the strongest risk factor for these disorders, hiPSC-derived models represent rejuvenated neurons. We developed hiPSC-derived Aged dopaminergic and cholinergic neurons to model PD and related synucleinopathies. Our new method induces aging through a `semi-natural' process, by passaging multiple times at the Neural Precursor Cell stage, prior to final differentiation. Characterization of isogenic hiPSC-derived neurons using heterochromatin and nuclear envelope markers, as well as DNA damage and global DNA methylation, validated our age-inducing method. Next, we compared neurons derived from a patient with SNCA-triplication (SNCA-Tri) and a Control. The SNCA-Tri neurons displayed exacerbated nuclear aging, showing advanced aging signatures already at the Juvenile stage. Noteworthy, the Aged SNCA-Tri neurons showed more α-synuclein aggregates per cell versus the Juvenile. We suggest a link between the effects of aging and SNCA overexpression on neuronal nuclear architecture.
人诱导多能干细胞（hiPSC）衍生模型已推动了神经退行性疾病的研究，包括帕金森病（PD）。虽然年龄是这些疾病的最强风险因素，但 hiPSC 衍生模型代表了年轻化的神经元。我们开发了 hiPSC 衍生的衰老多巴胺能和胆碱能神经元，以模拟 PD 和相关的突触核蛋白病。我们的新方法通过在神经前体细胞阶段多次传代的“半自然”过程诱导衰老，然后再进行最终分化。使用异染色质和核膜标记物以及 DNA 损伤和全基因组甲基化对同基因 hiPSC 衍生神经元进行特征分析，验证了我们的诱导衰老方法。接下来，我们比较了源自 SNCA 三倍体（SNCA-Tri）患者和对照的神经元。SNCA-Tri 神经元显示出核衰老加剧，在青少年期就已经显示出了衰老的特征。值得注意的是，与青少年期相比，衰老的 SNCA-Tri 神经元每个细胞中的α-突触核蛋白聚集物更多。我们认为衰老的影响与 SNCA 过表达对神经元核结构之间存在关联。
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