UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK.
The Francis Crick Institute, London, UK.
Nature. 2022 Mar;603(7899):131-137. doi: 10.1038/s41586-022-04436-3. Epub 2022 Feb 23.
Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.
UNC13A 是一种关键的突触功能基因，其变体增加了肌萎缩侧索硬化症和额颞叶痴呆的风险，这两种相关的神经退行性疾病的特征是 RNA 结合蛋白 TDP-43 的定位错误。在这里，我们表明 TDP-43 的耗竭诱导 UNC13A 中一个隐藏外显子的强烈包含，导致无意义介导的衰变和 UNC13A 蛋白的丢失。与肌萎缩侧索硬化症和额颞叶痴呆风险强烈相关的两种常见的内含子 UNC13A 多态性与 TDP-43 结合位点重叠。这些多态性增强了隐藏外显子的包含，无论是在培养的细胞中还是在这些病症患者的大脑和脊髓中。我们的研究结果表明，核 TDP-43 功能丧失与疾病之间存在遗传联系，揭示了 UNC13A 变体加剧 TDP-43 功能降低影响的机制。它们进一步为 TDP-43 蛋白病提供了一个有希望的治疗靶点。
