Identifying FUS amyotrophic lateral sclerosis disease signatures in patient dermal fibroblasts.

IF 10.7 1区 生物学 Q1 CELL BIOLOGY Developmental cell Pub Date : 2024-08-19 Epub Date: 2024-06-14 DOI:10.1016/j.devcel.2024.05.011
Karl Kumbier, Maike Roth, Zizheng Li, Julia Lazzari-Dean, Christopher Waters, Sabrina Hammerlindl, Capria Rinaldi, Ping Huang, Vladislav A Korobeynikov, Hemali Phatnani, Neil Shneider, Matthew P Jacobson, Lani F Wu, Steven J Altschuler
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Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, highly heterogeneous neurodegenerative disease, underscoring the importance of obtaining information to personalize clinical decisions quickly after diagnosis. Here, we investigated whether ALS-relevant signatures can be detected directly from biopsied patient fibroblasts. We profiled familial ALS (fALS) fibroblasts, representing a range of mutations in the fused in sarcoma (FUS) gene and ages of onset. To differentiate FUS fALS and healthy control fibroblasts, machine-learning classifiers were trained separately on high-content imaging and transcriptional profiles. "Molecular ALS phenotype" scores, derived from these classifiers, captured a spectrum from disease to health. Interestingly, these scores negatively correlated with age of onset, identified several pre-symptomatic individuals and sporadic ALS (sALS) patients with FUS-like fibroblasts, and quantified "movement" of FUS fALS and "FUS-like" sALS toward health upon FUS ASO treatment. Taken together, these findings provide evidence that non-neuronal patient fibroblasts can be used for rapid, personalized assessment in ALS.

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识别患者真皮成纤维细胞中的 FUS 肌萎缩侧索硬化症疾病特征。
肌萎缩性脊髓侧索硬化症(ALS)是一种进展迅速、高度异质性的神经退行性疾病,因此在确诊后迅速获得个性化临床决策的信息非常重要。在此,我们研究了能否直接从活检的患者成纤维细胞中检测到 ALS 相关特征。我们对家族性 ALS(fALS)成纤维细胞进行了分析,这些成纤维细胞代表了融合肉瘤(FUS)基因的一系列突变和发病年龄。为了区分 FUS fALS 和健康对照成纤维细胞,分别对高内容成像和转录图谱进行了机器学习分类器训练。从这些分类器中得出的 "分子 ALS 表型 "得分反映了从疾病到健康的范围。有趣的是,这些分数与发病年龄呈负相关,确定了一些症状前个体和散发性 ALS(sALS)患者的 FUS 样成纤维细胞,并量化了 FUS fALS 和 "FUS 样 "sALS 在接受 FUS ASO 治疗后向健康状态的 "移动"。总之,这些研究结果证明,非神经元患者成纤维细胞可用于 ALS 的快速、个性化评估。
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来源期刊
Developmental cell
Developmental cell 生物-发育生物学
CiteScore
18.90
自引率
1.70%
发文量
203
审稿时长
3-6 weeks
期刊介绍: Developmental Cell, established in 2001, is a comprehensive journal that explores a wide range of topics in cell and developmental biology. Our publication encompasses work across various disciplines within biology, with a particular emphasis on investigating the intersections between cell biology, developmental biology, and other related fields. Our primary objective is to present research conducted through a cell biological perspective, addressing the essential mechanisms governing cell function, cellular interactions, and responses to the environment. Moreover, we focus on understanding the collective behavior of cells, culminating in the formation of tissues, organs, and whole organisms, while also investigating the consequences of any malfunctions in these intricate processes.
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