Departments of Bioengineering, University of Washington, Seattle, Washington 98195.
Rehabilitation Medicine, University of Washington, Seattle, Washington 98195.
J Neurosci. 2024 Apr 17;44(16):e1787232024. doi: 10.1523/JNEUROSCI.1787-23.2024.
Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder marked by progressive motor neuron degeneration and muscle denervation. A recent transcriptomic study integrating a wide range of human ALS samples revealed that the upregulation of p53, a downstream target of inflammatory stress, is commonly detected in familial and sporadic ALS cases by a mechanism linked to a transactive response DNA-binding protein 43 (TDP-43) dysfunction. In this study, we show that prolonged interferon-gamma (IFNγ) treatment of human induced pluripotent stem cell-derived spinal motor neurons results in a severe cytoplasmic aggregation of TDP-43. TDP-43 dysfunction resulting from either IFNγ exposure or an ALS-associated TDP-43 mutation was associated with the activation of the p53 pathway. This was accompanied by the hyperactivation of neuronal firing, followed by the complete loss of their electrophysiological function. Through a comparative single-cell transcriptome analysis, we have identified significant alterations in ALS-associated genes in motor neurons exposed to IFNγ, implicating their direct involvement in ALS pathology. Interestingly, IFNγ was found to induce significant levels of programmed death-ligand 1 (PD-L1) expression in motor neurons without affecting the levels of any other immune checkpoint proteins. This finding suggests a potential role of excessive PD-L1 expression in ALS development, given that PD-L1 was recently reported to impair neuronal firing ability in mice. Our findings suggest that exposing motor neurons to IFNγ could directly derive ALS pathogenesis, even without the presence of the inherent genetic mutation or functional glia component. Furthermore, this study provides a comprehensive list of potential candidate genes for future immunotherapeutic targets with which to treat sporadic forms of ALS, which account for 90% of all reported cases.
肌萎缩侧索硬化症（ALS）是一种使人衰弱的神经退行性疾病，其特征是运动神经元进行性退化和肌肉失神经支配。最近的一项转录组研究整合了广泛的人类 ALS 样本，揭示了炎症应激的下游靶标 p53 的上调，在家族性和散发性 ALS 病例中通过与转激活反应 DNA 结合蛋白 43（TDP-43）功能障碍相关的机制普遍检测到。在这项研究中，我们表明，人类诱导多能干细胞衍生的脊髓运动神经元的干扰素-γ（IFNγ）长期处理导致 TDP-43 的严重细胞质聚集。IFNγ 暴露或与 ALS 相关的 TDP-43 突变导致的 TDP-43 功能障碍与 p53 途径的激活有关。这伴随着神经元放电的过度激活，随后完全丧失其电生理功能。通过比较单细胞转录组分析，我们已经确定了在 IFNγ 暴露的运动神经元中与 ALS 相关的基因发生了显著变化，这表明它们直接参与了 ALS 病理学。有趣的是，IFNγ 被发现可诱导运动神经元中程序性死亡配体 1（PD-L1）的显著表达，而不影响任何其他免疫检查点蛋白的水平。这一发现表明，PD-L1 表达过度可能在 ALS 发展中起作用，因为最近有报道称 PD-L1 会损害小鼠的神经元放电能力。我们的研究结果表明，即使没有内在的遗传突变或功能性神经胶质成分，IFNγ 暴露也可以直接导致 ALS 发病机制。此外，本研究提供了一个潜在的候选基因列表，这些基因可能成为未来治疗所有报告病例中占 90%的散发型 ALS 的免疫治疗靶点。
