Lin Lin, Göke Jonathan, Cukuroglu Engin, Dranias Mark R, VanDongen Antonius M J, Stanton Lawrence W
NUS Graduate School for Integrative Sciences and Engineering, Singapore 117456, Singapore; Stem Cell and Regenerative Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore.
Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
Cell Rep. 2016 Jun 14;15(11):2411-26. doi: 10.1016/j.celrep.2016.05.022. Epub 2016 Jun 2.
The fact that Parkinson's disease (PD) can arise from numerous genetic mutations suggests a unifying molecular pathology underlying the various genetic backgrounds. To address this hypothesis, we took an integrated approach utilizing in vitro disease modeling and comprehensive transcriptome profiling to advance our understanding of PD progression and the concordant downstream signaling pathways across divergent genetic predispositions. To model PD in vitro, we generated neurons harboring disease-causing mutations from patient-specific, induced pluripotent stem cells (iPSCs). We observed signs of degeneration in midbrain dopaminergic neurons, reflecting the cardinal feature of PD. Gene expression signatures of PD neurons provided molecular insights into disease phenotypes observed in vitro, including oxidative stress vulnerability and altered neuronal activity. Notably, PD neurons show that elevated RBFOX1, a gene previously linked to neurodevelopmental diseases, underlies a pattern of alternative RNA-processing associated with PD-specific phenotypes.
帕金森病（PD）可由多种基因突变引发，这一事实表明在不同的遗传背景下存在统一的分子病理学机制。为验证这一假设，我们采用了一种综合方法，利用体外疾病模型和全面的转录组分析，以加深对PD进展以及不同遗传易感性下一致的下游信号通路的理解。为在体外模拟PD，我们从患者特异性诱导多能干细胞（iPSC）中生成了携带致病突变的神经元。我们观察到中脑多巴胺能神经元出现退化迹象，这反映了PD的主要特征。PD神经元的基因表达特征为体外观察到的疾病表型提供了分子层面的见解，包括氧化应激易感性和神经元活动改变。值得注意的是，PD神经元显示出RBFOX1升高，该基因先前与神经发育疾病有关，它构成了与PD特异性表型相关的一种可变RNA加工模式的基础。
