Novel monoclonal antibodies to normal and pathologically altered human TDP-43 proteins
Novel monoclonal antibodies to normal and pathologically altered human TDP-43 proteins
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DOI：
10.1186/2051-5960-2-33
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发表时间：
2014-01-01
影响因子：
7.1
通讯作者：
Lee, Virginia M. Y.
中科院分区：
文献类型：
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作者：
Kwong, Linda K.;Irwin, David J.;Lee, Virginia M. Y.
RNA/DNA 结合蛋白 TDP-43 是肌萎缩侧索硬化症 (ALS) 和大多数额颞叶变性 (FTLD-TDP)（统称为 TDP-43 蛋白病）特有的泛素化包涵体的关键成分。为了进一步阐明病理性 TDP-43 加工机制并鉴定可用作 TDP-43 蛋白病潜在生物标志物的 TDP-43 表位，我们开发了一组新型单克隆抗体 (MAb)，针对延伸至 TDP-43 长度的区域。在这里，我们证实了之前的观察结果，即人 TDP-43 蛋白病组织的新皮质内含物中没有或极少有 TDP-43 N 端结构域的积累，并且我们鉴定了这些 MAb 的一个子集，这些 MAb 对人与小鼠 TDP-43 具有特异性。值得注意的是，这些 MAb 之一识别的表位优先检测病理性 TDP-43 内含物，对正常核 TDP-43 的反应性可忽略不计，类似于仅结合病理性 TDP-43 的抗磷酸化 TDP-43 特异性抗体。因此，我们推断这种新的 MAb 可识别异常 TDP-43 中的磷酸化独立但疾病特异性的病理构象。这些数据表明，本文报道的新型单克隆抗体将有助于以患者为导向的研究以及基于动物和细胞的 TDP-43 蛋白病模型（包括 ALS 和 FTLD-TDP）的研究。
The RNA/DNA-binding protein, TDP-43, is the key component of ubiquitinated inclusions characteristic of amyotrophic lateral sclerosis (ALS) and the majority of frontotemporal lobar degeneration (FTLD-TDP) referred to collectively as TDP-43 proteinopathies. To further elucidate mechanisms of pathological TDP-43 processing and identify TDP-43 epitopes that could be useful as potential biomarkers of TDP-43 proteinopathies, we developed a panel of novel monoclonal antibodies (MAbs) directed at regions extending across the length of TDP-43. Here, we confirm previous observations that there is no or minimal accumulation of TDP-43 N-terminal domains in neocortical inclusions in human TDP-43 proteinopathy tissues and we identify a subset of these MAbs that are specific for human versus mouse TDP-43. Notably, one of these MAbs recognized an epitope that preferentially detected pathological TDP-43 inclusions with negligible reactivity for normal nuclear TDP-43 resembling anti-phospho-TDP-43 specific antibodies that only bind pathological TDP-43. Hence, we infer that this new MAb recognizes a phosphorylation independent but disease-specific pathologic conformation in abnormal TDP-43. These data suggest that the novel MAbs reported here will be useful for patient-oriented research as well as for studies of animal and cell-based models of TDP-43 proteinopathies including ALS and FTLD-TDP.