Department of Neurology, University of Utah, Salt Lake City, UT.
Ann Neurol. 2021 Jun;89(6):1114-1128. doi: 10.1002/ana.26069. Epub 2021 Apr 8.
Mutations in the ATXN2 gene (CAG expansions ≥32 repeats) can be a rare cause of Parkinson's disease and amyotrophic lateral sclerosis (ALS). We recently reported that the stress granule (SG) protein Staufen1 (STAU1) was overabundant in neurodegenerative disorder spinocerebellar ataxia type 2 (SCA2) patient cells, animal models, and ALS-TDP-43 fibroblasts, and provided a link between SG formation and autophagy. We aimed to test if STAU1 overabundance has a role in the pathogenesis of other neurodegenerative diseases.
With multiple neurodegenerative patient-derived cell models, animal models, and human postmortem ALS tissue, we evaluate STAU1 function using biochemical and immunohistological analyses.
We demonstrate STAU1 overabundance and increased total and phosphorylated mammalian target of rapamycin (mTOR) in fibroblast cells from patients with ALS with mutations in TDP-43, patients with dementia with PSEN1 mutations, a patient with parkinsonism with MAPT mutation, Huntington's disease (HD) mutations, and SCA2 mutations. Increased STAU1 levels and mTOR activity were seen in human ALS spinal cord tissues as well as in animal models. Changes in STAU1 and mTOR protein levels were post-transcriptional. Exogenous expression of STAU1 in wildtype cells was sufficient to activate mTOR and downstream targets and form SGs. Targeting STAU1 by RNAi normalized mTOR, suggesting a potential role for therapy in diseases associated with STAU1 overabundance.
STAU1 overabundance in neurodegeneration is a common phenomenon associated with hyperactive mTOR. Targeting STAU1 with ASOs or miRNA viral vectors may represent a novel, efficacious therapy for neurodegenerative diseases characterized by overabundant STAU1. ANN NEUROL 2021;89:1114-1128.
ATXN2 基因（CAG 扩展≥32 个重复）中的突变可能是帕金森病和肌萎缩侧索硬化症（ALS）的罕见病因。我们最近报道称，神经退行性疾病脊髓小脑共济失调 2 型（SCA2）患者细胞、动物模型和 ALS-TDP-43 成纤维细胞中应激颗粒（SG）蛋白 Staufen1（STAU1）过度表达，并提供了 SG 形成与自噬之间的联系。我们旨在测试 STAU1 过度表达是否在其他神经退行性疾病的发病机制中起作用。
通过多种神经退行性疾病患者来源的细胞模型、动物模型和人类 ALS 死后组织，我们使用生化和免疫组织化学分析来评估 STAU1 的功能。
我们在 TDP-43 突变的 ALS 患者、PSEN1 突变的痴呆症患者、MAPT 突变的帕金森症患者、亨廷顿病（HD）突变和 SCA2 突变的患者的成纤维细胞中观察到 STAU1 过度表达和总 mTOR 及其磷酸化增加。人类 ALS 脊髓组织以及动物模型中也观察到 STAU1 水平升高和 mTOR 活性增加。STAU1 和 mTOR 蛋白水平的变化是转录后发生的。在野生型细胞中外源表达 STAU1 足以激活 mTOR 及其下游靶标并形成 SG。通过 RNAi 靶向 STAU1 可使 mTOR 正常化，这表明针对 STAU1 过度表达的疾病的治疗可能具有潜在作用。
神经退行性变中 STAU1 过度表达是与 mTOR 过度活跃相关的普遍现象。用 ASO 或 miRNA 病毒载体靶向 STAU1 可能代表一种针对以 STAU1 过度表达为特征的神经退行性疾病的新型有效治疗方法。
