Leykam Laura, Jonsson P Andreas, Forsberg Karin M E, Andersen Peter M, Brännström Thomas, Marklund Stefan L, Zetterström Per
Department of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden.
Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
J Neurochem. 2025 Jun;169(6):e70136. doi: 10.1111/jnc.70136.
Gene silencing therapy is an effective treatment for amyotrophic lateral sclerosis (ALS) patients carrying mutations in the superoxide dismutase-1 (SOD1) gene aiming to reduce noxious forms of SOD1 in the central nervous system (CNS). The normal steady-state level of SOD1 protein in human CNS is therefore of interest but is contested. In this work we have analyzed SOD1 protein content, total protein content, and SOD1 enzymatic activity in six areas of the CNS as well as in four peripheral tissues from sporadic and familial ALS patients and non-ALS controls. Our results show that SOD1 in the human CNS constitutes around 100 μg/g wet weight corresponding to about 0.16% of the total protein in the studied areas. Of the peripheral tissues analyzed, kidney and erythrocytes contain roughly equal amounts, liver higher, and skeletal muscle lower levels of SOD1 compared to the CNS. This data shows SOD1 protein levels around 10 times lower compared to previously published figures. However, SOD1 can still be considered an abundant protein considering that > 12 000 proteins are expressed in human cells. There was no difference in SOD1 protein content between sporadic or familial ALS patients and control individuals. The level and activity of SOD1 are not deviating in the areas of the CNS that are most vulnerable to ALS. Instead, insufficient control of SOD1 structure and aggregation could be important factors behind the vulnerability of motor areas to SOD1 proteotoxicity.
基因沉默疗法是治疗携带超氧化物歧化酶1（SOD1）基因突变的肌萎缩侧索硬化症（ALS）患者的一种有效疗法，旨在减少中枢神经系统（CNS）中有害形式的SOD1。因此，人类中枢神经系统中SOD1蛋白的正常稳态水平备受关注，但存在争议。在这项研究中，我们分析了散发性和家族性ALS患者以及非ALS对照者的中枢神经系统六个区域以及四个外周组织中的SOD1蛋白含量、总蛋白含量和SOD1酶活性。我们的结果表明，人类中枢神经系统中的SOD1含量约为100μg/g湿重，约占研究区域总蛋白的0.16%。在所分析的外周组织中，与中枢神经系统相比，肾脏和红细胞中的SOD1含量大致相等，肝脏中的含量较高，骨骼肌中的含量较低。该数据表明，SOD1蛋白水平比先前公布的数字低约10倍。然而，考虑到人类细胞中表达的蛋白质超过12000种，SOD1仍可被视为一种丰富的蛋白质。散发性或家族性ALS患者与对照个体之间的SOD1蛋白含量没有差异。在中枢神经系统中最易受ALS影响的区域，SOD1的水平和活性并没有偏差。相反，对SOD1结构和聚集的控制不足可能是运动区域易受SOD1蛋白毒性影响的重要因素。
