Targeting the TDP-43 low complexity domain blocks spreading of pathology in a mouse model of ALS/FTD.

IF 6.2 2区 医学 Q1 NEUROSCIENCES Acta Neuropathologica Communications Pub Date : 2024-10-03 DOI:10.1186/s40478-024-01867-z
Elodie Chevalier, Mickael Audrain, Monisha Ratnam, Romain Ollier, Aline Fuchs, Kasia Piorkowska, Andrea Pfeifer, Marie Kosco-Vilbois, Tamara Seredenina, Tariq Afroz
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Abstract

Abnormal cytoplasmic localization and accumulation of pathological transactive response DNA binding protein of 43 kDa (TDP-43) underlies several devastating diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). A key element is the correlation between disease progression and spatio-temporal propagation of TDP-43-mediated pathology in the central nervous system. Several lines of evidence support the concept of templated aggregation and cell to cell spreading of pathological TDP-43. To further investigate this mechanism in vivo, we explored the efficacy of capturing and masking the seeding-competent region of extracellular TDP-43 species. For this, we generated a novel monoclonal antibody (mAb), ACI-6677, that targets the pathogenic protease-resistant amyloid core of TDP-43. ACI-6677 has a picomolar binding affinity for TDP-43 and is capable of binding to all C-terminal TDP-43 fragments. In vitro, ACI-6677 inhibited TDP-43 aggregation and boosted removal of pathological TDP-43 aggregates by phagocytosis. When injecting FTLD-TDP brain extracts unilaterally in the CamKIIa-hTDP-43NLSm mouse model, ACI-6677 significantly limited the induction of phosphorylated TDP-43 (pTDP-43) inclusions. Strikingly, on the contralateral side, the mAb significantly prevented pTDP-43 inclusion appearance exemplifying blocking of the spreading process. Taken together, these data demonstrate for the first time that an immunotherapy targeting the protease-resistant amyloid core of TDP-43 has the potential to restrict spreading, substantially slowing or stopping progression of disease.

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靶向 TDP-43 低复杂性结构域可阻止 ALS/FTD 小鼠模型的病理扩散。
43 kDa 的病理性转录反应 DNA 结合蛋白(TDP-43)的异常胞质定位和积累是肌萎缩性脊髓侧索硬化症(ALS)和伴有 TDP-43 病理变化的额颞叶变性(FTLD-TDP)等几种毁灭性疾病的基础。其中一个关键因素是疾病进展与 TDP-43 介导的病理学在中枢神经系统中的时空传播之间的相关性。一些证据支持病理 TDP-43 模板化聚集和细胞间传播的概念。为了进一步研究这一体内机制,我们探索了捕获和掩盖细胞外 TDP-43 物种的播种能力区域的功效。为此,我们生成了一种新型单克隆抗体(mAb)--ACI-6677,它以致病性蛋白酶抗性淀粉样核心 TDP-43 为靶标。ACI-6677 与 TDP-43 的结合亲和力为皮摩尔,能够与 TDP-43 的所有 C 端片段结合。在体外,ACI-6677 可抑制 TDP-43 的聚集,并通过吞噬作用促进病理 TDP-43 聚集的清除。在CamKIIa-hTDP-43NLSm小鼠模型中单侧注射FTLD-TDP脑提取物时,ACI-6677能显著限制磷酸化TDP-43(pTDP-43)包涵体的诱导。令人震惊的是,在小鼠对侧,该 mAb 能明显阻止 pTDP-43 包涵体的出现,体现了对扩散过程的阻断。总之,这些数据首次证明,针对 TDP-43 蛋白酶抗性淀粉样核心的免疫疗法有可能限制扩散,从而大大减缓或阻止疾病的进展。
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来源期刊
Acta Neuropathologica Communications
Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine
CiteScore
11.20
自引率
2.80%
发文量
162
审稿时长
8 weeks
期刊介绍: "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.
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