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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-023-02788-5

摘要内容如下：

尽管在肌萎缩侧索硬化（ALS）和额颞叶痴呆（FTD）的死后组织中，TAR DNA结合蛋白43kDa（TDP-43）剪接抑制的缺失得到了很好的证明，但这种异常是否发生在疾病早期仍未解决。隐性外显子包含反映了TDP-43功能的丧失，因此检测脑脊液（CSF）或血液中含有隐性外显子编码的新表位的蛋白质可以揭示患者TDP-43失调的最早阶段。在这里，我们使用一种新鉴定的单克隆抗体，该抗体对TDP-43依赖性隐蔽表位（由HDGFL2中发现的隐蔽外显子编码）具有特异性，以显示TDP-43剪接抑制的缺失发生在ALS-FTD中，包括症状前C9orf72突变携带者。隐匿性肝癌衍生生长因子样蛋白2（HDGFL2）在家族性ALS-FTD和散发性ALS患者脑脊液中的累积水平显著高于对照组，并且在家族性疾病中的升高早于神经丝轻链和磷酸化神经丝重链蛋白水平。隐匿性HDGFL2也可在ALS-FTD个体（包括症状前C9orf72突变携带者）的血液中检测到，其累积水平与CSF中的水平高度相关。我们的研究结果表明，TDP-43隐匿性剪接抑制的缺失发生在疾病进展的早期，甚至是症状前，并且HDGFL2隐匿性新表位的检测可作为ALS的潜在诊断生物标志物，这将有助于临床试验中患者的招募和靶标参与的测量。

英文原文如下：

Abstracts

Although loss of TAR DNA-binding protein 43 kDa (TDP-43) splicing repression is well documented in postmortem tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), whether this abnormality occurs during early-stage disease remains unresolved. Cryptic exon inclusion reflects loss of function of TDP-43, and thus detection of proteins containing cryptic exon-encoded neoepitopes in cerebrospinal fluid (CSF) or blood could reveal the earliest stages of TDP-43 dysregulation in patients. Here we use a newly characterized monoclonal antibody specific to a TDP-43-dependent cryptic epitope (encoded by the cryptic exon found in HDGFL2) to show that loss of TDP-43 splicing repression occurs in ALS-FTD, including in presymptomatic C9orf72 mutation carriers. Cryptic hepatoma-derived growth factor-like protein 2 (HDGFL2) accumulates in CSF at significantly higher levels in familial ALS-FTD and sporadic ALS compared with controls and is elevated earlier than neurofilament light and phosphorylated neurofilament heavy chain protein levels in familial disease. Cryptic HDGFL2 can also be detected in blood of individuals with ALS-FTD, including in presymptomatic C9orf72 mutation carriers, and accumulates at levels highly correlated with those in CSF. Our findings indicate that loss of TDP-43 cryptic splicing repression occurs early in disease progression, even presymptomatically, and that detection of the HDGFL2 cryptic neoepitope serves as a potential diagnostic biomarker for ALS, which should facilitate patient recruitment and measurement of target engagement in clinical trials.

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