Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
Cell Rep. 2022 Oct 25;41(4):111505. doi: 10.1016/j.celrep.2022.111505.
Gene-based therapeutic strategies to lower ataxin-2 levels are emerging for the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2). Additional strategies to lower levels of ataxin-2 could be beneficial. Here, we perform a genome-wide arrayed small interfering RNA (siRNA) screen in human cells and identify RTN4R, the gene encoding the RTN4/NoGo-Receptor, as a potent modifier of ataxin-2 levels. RTN4R knockdown, or treatment with a peptide inhibitor, is sufficient to lower ataxin-2 protein levels in mouse and human neurons in vitro, and Rtn4r knockout mice have reduced ataxin-2 levels in vivo. We provide evidence that ataxin-2 shares a role with the RTN4/NoGo-Receptor in limiting axonal regeneration. Reduction of either protein increases axonal regrowth following axotomy. These data define the RTN4/NoGo-Receptor as a novel therapeutic target for ALS and SCA2 and implicate the targeting of ataxin-2 as a potential treatment following nerve injury.
针对神经退行性疾病肌萎缩侧索硬化症（ALS）和脊髓小脑共济失调 2 型（SCA2），出现了基于基因的治疗策略来降低ataxin-2 的水平。降低 ataxin-2 水平的其他策略可能也有益处。在这里，我们在人类细胞中进行了全基因组阵列小分子干扰 RNA（siRNA）筛选，鉴定出编码 RTN4/NoGo 受体的 RTN4R 基因是降低 ataxin-2 水平的有效调节剂。RTN4R 敲低或使用肽抑制剂处理足以降低体外培养的小鼠和人类神经元中的 ataxin-2 蛋白水平，并且 Rtn4r 敲除小鼠体内的 ataxin-2 水平降低。我们提供的证据表明，ataxin-2 在限制轴突再生方面与 RTN4/NoGo 受体具有相同的作用。减少任一蛋白均可增加轴突切断后的轴突再生。这些数据将 RTN4/NoGo 受体定义为 ALS 和 SCA2 的新治疗靶点，并暗示靶向 ataxin-2 可能是神经损伤后的一种潜在治疗方法。
