Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Autophagy. 2020 Apr;16(4):672-682. doi: 10.1080/15548627.2019.1635379. Epub 2019 Jul 7.
A shared neuropathological hallmark in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is nuclear clearance and cytoplasmic aggregation of TARDBP/TDP-43 (TAR DNA binding protein). We previously showed that the ability of TARDBP to repress nonconserved cryptic exons was impaired in brains of patients with ALS and FTD, suggesting that its nuclear depletion contributes to neurodegeneration. However, the critical pathways impacted by the failure to repress cryptic exons that may contribute to neurodegeneration remain undefined. Here, we report that transcriptome analysis of TARDBP-deficient neurons revealed downregulation of , a critical gene required for macroautophagy/autophagy. Mouse and models lacking TARDBP/TBPH in motor neurons exhibiting age-dependent neurodegeneration and motor deficits showed reduction of ATG7 and accumulation of SQSTM1/p62 inclusions. Importantly, genetic upregulation of the autophagy pathway improved motor function and survival in TBPH-deficient flies. Together with our observation that ATG7 is reduced in ALS-FTD brain tissues, these findings identify the autophagy pathway as one key effector of nuclear depletion of TARDBP that contributes to neurodegeneration. We thus suggest that the autophagy pathway is a therapeutic target for ALS-FTD and other disorders exhibiting TARDBP pathology. ALS: amyotrophic lateral sclerosis; ANOVA: analysis of variance; ChAT: choline acetyltransferase; CTSD: cathepsin D; FTD: frontotemporal dementia; LAMP1: lysosomal associated membrane protein 1; NMJ: neuromuscular junction; RBFOX3/NeuN: RNA binding fox-1 homolog 3; SQSTM1: sequestosome 1; TARDBP/TDP-43: TAR DNA binding protein 43.
在肌萎缩性侧索硬化症（ALS）和额颞叶痴呆（FTD）中，存在一个共同的神经病理学特征，即 TARDBP/TDP-43（TAR DNA 结合蛋白）的核清除和细胞质聚集。我们之前曾表明，TARDBP 抑制非保守隐蔽外显子的能力在 ALS 和 FTD 患者的大脑中受损，这表明其核耗竭有助于神经退行性变。然而，由于未能抑制可能导致神经退行性变的隐蔽外显子而受到影响的关键途径仍未定义。在这里，我们报告称，TARDBP 缺陷神经元的转录组分析显示， 下调，这是巨自噬/自噬所必需的关键基因。在运动神经元中缺乏 TARDBP/TBPH 的小鼠和 模型表现出年龄依赖性的神经退行性变和运动功能障碍，其 ATG7 减少，SQSTM1/p62 包涵体积累。重要的是，TBPH 缺陷果蝇中自噬途径的遗传上调改善了其运动功能和生存。结合我们在 ALS-FTD 脑组织中观察到的 ATG7 减少的发现，这些结果表明自噬途径是 TARDBP 核耗竭导致神经退行性变的关键效应途径之一。因此，我们认为自噬途径是治疗 ALS-FTD 和其他表现出 TARDBP 病理的疾病的一个治疗靶点。ALS：肌萎缩性侧索硬化症；ANOVA：方差分析；ChAT：胆碱乙酰转移酶；CTSD：组织蛋白酶 D；FTD：额颞叶痴呆；LAMP1：溶酶体相关膜蛋白 1；NMJ：神经肌肉接头；RBFOX3/NeuN：RNA 结合 FOX-1 同源物 3；SQSTM1：自噬相关蛋白 1；TARDBP/TDP-43：TAR DNA 结合蛋白 43。
