Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.
Department of Neurology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.
J Neurol. 2022 Sep;269(9):4863-4871. doi: 10.1007/s00415-022-11126-7. Epub 2022 May 3.
Recent evidence points toward a role of the small ubiquitin-like modifier (SUMO) system, including SUMO4, in protecting from stress insults and neurodegeneration, such as the progressive motor neuron disease amyotrophic lateral sclerosis (ALS), e.g., by regulating stress granule (SG) dynamics. Here, we investigated whether SUMO4 variants play a role in ALS pathogenesis.
Whole-exome or targeted SUMO4 sequencing was done in 222 unrelated European ALS patients. The consequences of the identified initiator codon variant were analyzed at the mRNA, protein and cellular level. SUMO4 expression was quantified in human tissues. All patients were subjected to clinical, electrophysiological, and neuroradiological characterization.
A rare heterozygous SUMO4 variant, i.e., SUMO4:c.2T>C p.Met1?, was detected in four of 222 (1.8%) ALS patients, significantly more frequently than in two control cohorts (0.3% each). SUMO4 mRNA and protein expression was diminished in whole blood or fibroblasts of a SUMO4 variant carrier versus controls. Pertinent stress factors, i.e., head trauma or cancer (treated by radiochemotherapy), were significantly more frequent in SUMO4 variant carrier versus non-carrier ALS patients. The mean number of SGs per cell was significantly higher in fibroblasts of a SUMO4 variant carrier compared to controls at baseline, upon oxidative stress, and after recovery, and SUMOylation of ALS-associated valosin-containing protein by SUMO4 was decreased. SUMO4 mRNA expression was highest in brain of all human tissues analyzed.
Our results are consistent with SUMO4 haploinsufficiency as a contributor to ALS pathogenesis impacting SG dynamics and possibly acting in conjunction with environmental oxidative stress-related factors.
最近的证据表明，小泛素样修饰物（SUMO）系统，包括 SUMO4，在保护免受应激损伤和神经退行性变方面发挥作用，例如，在进行性运动神经元疾病肌萎缩侧索硬化症（ALS）中，通过调节应激颗粒（SG）的动态。在这里，我们研究了 SUMO4 变体是否在 ALS 发病机制中起作用。
对 222 名无关的欧洲 ALS 患者进行全外显子或靶向 SUMO4 测序。在 mRNA、蛋白质和细胞水平上分析鉴定的起始密码子变异的后果。在人类组织中定量 SUMO4 表达。所有患者均接受临床、电生理和神经影像学特征分析。
在 222 名 ALS 患者中的 4 名（1.8%）中检测到罕见的杂合 SUMO4 变体，即 SUMO4:c.2T>C p.Met1?，明显高于两个对照队列（各 0.3%）。与对照相比，携带 SUMO4 变体的个体的全血或成纤维细胞中 SUMO4 mRNA 和蛋白表达减少。与非携带者相比，携带 SUMO4 变体的 ALS 患者的相关应激因素，即头部创伤或癌症（经放化疗治疗）明显更为常见。与对照相比，携带 SUMO4 变体的成纤维细胞中的 SG 数量在基线、氧化应激后和恢复后均显著增加，并且 SUMO4 对 ALS 相关的含缬氨酸蛋白的 SUMOylation 减少。在分析的所有人类组织中，SUMO4 mRNA 表达在大脑中最高。
我们的结果与 SUMO4 单倍不足作为 ALS 发病机制的一个贡献者一致，该贡献者影响 SG 动态，并且可能与环境氧化应激相关因素一起起作用。
