Departments of Immunology.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
J Neurosci. 2018 Mar 7;38(10):2615-2630. doi: 10.1523/JNEUROSCI.2282-17.2018. Epub 2018 Feb 7.
Members of the SCY1-like (SCYL) family of protein kinases are evolutionarily conserved and ubiquitously expressed proteins characterized by an N-terminal pseudokinase domain, centrally located Huntingtin, elongation factor 3, protein phosphatase 2A, yeast kinase TOR1 repeats, and an overall disorganized C-terminal segment. In mammals, three family members encoded by genes , , and have been described. Studies have pointed to a role for SCYL1 and SCYL2 in regulating neuronal function and viability in mice and humans, but little is known about the biological function of SCYL3. Here, we show that the biochemical and cell biological properties of SCYL3 are similar to those of SCYL1 and both proteins work in conjunction to maintain motor neuron viability. Specifically, although lack of in mice has no apparent effect on embryogenesis and postnatal life, it accelerates the onset of the motor neuron disorder caused by deficiency. Growth abnormalities, motor dysfunction, hindlimb paralysis, muscle wasting, neurogenic atrophy, motor neuron degeneration, and loss of large-caliber axons in peripheral nerves occurred at an earlier age in /S double-deficient mice than in -deficient mice. Disease onset also correlated with the mislocalization of TDP-43 in spinal motor neurons, suggesting that SCYL1 and SCYL3 regulate TDP-43 proteostasis. Together, our results demonstrate an overlapping role for SCYL1 and SCYL3 and highlight the importance the SCYL family of proteins in regulating neuronal function and survival. Only male mice were used in this study. SCYL1 and SCYL2, members of the SCY1-like family of pseudokinases, have well established roles in neuronal function. Herein, we uncover the role of SCYL3 in maintaining motor neuron viability. Although targeted disruption of in mice had little or no effect on embryonic development and postnatal life, it accelerated disease onset associated with the loss of , a novel motor neuron disease gene in humans. and double-deficient mice had neuronal defects characteristic of amyotrophic lateral sclerosis, including TDP-43 pathology, at an earlier age than did -deficient mice. Thus, we show that SCYL1 and SCYL3 play overlapping roles in maintaining motor neuronal viability and confirm that SCYL family members are critical regulators of neuronal function and survival.
SCY1 样蛋白激酶家族（SCYL）的成员是进化上保守的和普遍表达的蛋白，其特征是 N 端假激酶结构域、中央定位的亨廷顿蛋白、伸长因子 3、蛋白磷酸酶 2A、酵母激酶 TOR1 重复序列和整体无序的 C 端片段。在哺乳动物中，由基因编码的三个家族成员 、 和 已经被描述。研究表明，SCYL1 和 SCYL2 在调节小鼠和人类神经元功能和存活方面发挥作用，但对 SCYL3 的生物学功能知之甚少。在这里，我们表明 SCYL3 的生化和细胞生物学特性与 SCYL1 相似，并且这两种蛋白协同作用以维持运动神经元的存活。具体而言，尽管在小鼠中缺乏 对胚胎发生和出生后的生活没有明显影响，但它加速了由 缺乏引起的运动神经元疾病的发作。生长异常、运动功能障碍、后肢瘫痪、肌肉萎缩、神经源性萎缩、运动神经元退化以及周围神经中大纤维轴突的丢失在 /S 双缺陷小鼠中比 - 缺陷小鼠更早发生。疾病发作也与 TDP-43 在脊髓运动神经元中的定位错误相关，这表明 SCYL1 和 SCYL3 调节 TDP-43 的蛋白质稳态。总之，我们的结果证明了 SCYL1 和 SCYL3 的重叠作用，并强调了 SCYL 家族蛋白在调节神经元功能和存活中的重要性。本研究仅使用雄性小鼠。SCY1 样家族的假激酶成员 SCYL1 和 SCYL2 在神经元功能中具有明确的作用。在此，我们揭示了 SCYL3 在维持运动神经元存活中的作用。尽管在小鼠中靶向破坏 几乎没有或没有影响胚胎发育和出生后的生活，但它加速了与人类新型运动神经元疾病基因 缺失相关的疾病发作。 和 双缺陷小鼠在比 - 缺陷小鼠更早的年龄出现类似于肌萎缩侧索硬化症的神经元缺陷，包括 TDP-43 病理学。因此，我们表明 SCYL1 和 SCYL3 在维持运动神经元存活中发挥重叠作用，并证实 SCYL 家族成员是神经元功能和存活的关键调节剂。
