Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Biomarkers, Clinical Sciences Biogen, Cambridge, MA, 02142, USA.
Nat Commun. 2022 May 19;13(1):2799. doi: 10.1038/s41467-022-30387-4.
GGGGCC repeat expansion in C9ORF72, which can be translated in both sense and antisense directions into five dipeptide repeat (DPR) proteins, including poly(GP), poly(GR), and poly(GA), is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we developed sensitive assays that can detect poly(GA) and poly(GR) in the cerebrospinal fluid (CSF) of patients with C9ORF72 mutations. CSF poly(GA) and poly(GR) levels did not correlate with age at disease onset, disease duration, or rate of decline of ALS Functional Rating Scale, and the average levels of these DPR proteins were similar in symptomatic and pre-symptomatic patients with C9ORF72 mutations. However, in a patient with C9ORF72-ALS who was treated with antisense oligonucleotide (ASO) targeting the aberrant C9ORF72 transcript, CSF poly(GA) and poly(GR) levels decreased approximately 50% within 6 weeks, indicating they may serve as sensitive fluid-based biomarkers in studies directed against the production of GGGGCC repeat RNAs or DPR proteins.
C9ORF72 中的 GGGGCC 重复扩展可以正反义两种方式翻译成五种二肽重复（DPR）蛋白，包括 poly(GP)、poly(GR)和 poly(GA)，是肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）最常见的遗传原因。在这里，我们开发了灵敏的检测方法，可以检测 C9ORF72 突变患者的脑脊液（CSF）中的 poly(GA)和 poly(GR)。CSF poly(GA)和 poly(GR)水平与疾病发病年龄、疾病持续时间或 ALS 功能评定量表的下降率无关，这些 DPR 蛋白的平均水平在有 C9ORF72 突变的有症状和无症状患者中相似。然而，在一位接受针对异常 C9ORF72 转录本的反义寡核苷酸（ASO）治疗的 C9ORF72-ALS 患者中，CSF poly(GA)和 poly(GR)水平在 6 周内下降了约 50%，表明它们可能作为针对 GGGGCC 重复 RNA 或 DPR 蛋白产生的敏感液基生物标志物在研究中发挥作用。
