Victor Matheus B, Richner Michelle, Olsen Hannah E, Lee Seong Won, Monteys Alejandro M, Ma Chunyu, Huh Christine J, Zhang Bo, Davidson Beverly L, Yang X William, Yoo Andrew S
Department of Developmental Biology, Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Graduate Program in Neuroscience, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, USA.
Nat Neurosci. 2018 Mar;21(3):341-352. doi: 10.1038/s41593-018-0075-7. Epub 2018 Feb 5.
In Huntington's disease (HD), expansion of CAG codons in the huntingtin gene (HTT) leads to the aberrant formation of protein aggregates and the differential degeneration of striatal medium spiny neurons (MSNs). Modeling HD using patient-specific MSNs has been challenging, as neurons differentiated from induced pluripotent stem cells are free of aggregates and lack an overt cell death phenotype. Here we generated MSNs from HD patient fibroblasts through microRNA-based direct neuronal conversion, bypassing the induction of pluripotency and retaining age signatures of the original fibroblasts. We found that patient MSNs consistently exhibited mutant HTT (mHTT) aggregates, mHTT-dependent DNA damage, mitochondrial dysfunction and spontaneous degeneration in culture over time. We further provide evidence that erasure of age stored in starting fibroblasts or neuronal conversion of presymptomatic HD patient fibroblasts results in differential manifestation of cellular phenotypes associated with HD, highlighting the importance of age in modeling late-onset neurological disorders.
在亨廷顿舞蹈病(HD)中,亨廷顿蛋白基因(HTT)中CAG密码子的扩增会导致蛋白质聚集体异常形成以及纹状体中等棘状神经元(MSN)的差异性退化。使用患者特异性MSN对HD进行建模一直具有挑战性,因为从诱导多能干细胞分化而来的神经元没有聚集体,并且缺乏明显的细胞死亡表型。在这里,我们通过基于微小RNA的直接神经元转化,从HD患者成纤维细胞生成了MSN,绕过了多能性诱导并保留了原始成纤维细胞的年龄特征。我们发现,患者MSN在培养过程中始终表现出突变型HTT(mHTT)聚集体、mHTT依赖性DNA损伤、线粒体功能障碍和自发性退化。我们进一步提供证据表明,消除起始成纤维细胞中存储的年龄或对症状前HD患者成纤维细胞进行神经元转化会导致与HD相关的细胞表型的不同表现,突出了年龄在模拟迟发性神经疾病中的重要性。
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