Tokuda Eiichi, Leykam Laura, Zetterström Per, Brännström Thomas, Andersen Peter M, Marklund Stefan L
Department of Medical Biosciences, Umeå University, Umeå, SE 901 85, Sweden.
Laboratory of Clinical Medicine, School of Pharmacy, Nihon University, 7-7-1, Narashinodai, Funabashi, Chiba 274-8555, Japan.
Hum Mol Genet. 2025 Aug 16;34(16):1380-1391. doi: 10.1093/hmg/ddaf088.
Mutations in superoxide dismutase-1 (SOD1) are a common cause of amyotrophic lateral sclerosis (ALS). Inheritance is as a rule dominant, but in carriers of the most common mutation, D90A, disease can develop in both homozygous and, more rarely, in heterozygous individuals with unexplained differences in clinical presentation. There is mounting evidence that prion-like spread of SOD1 aggregation is the primary cause of the disease. Two different strains of aggregates have been found to arise in human SOD1 (hSOD1) transgenic mouse models of ALS. Strain A is formed by most mutants including hSOD1G85R and hSOD1WT, whereas hSOD1D90A transgenic mice form a distinct strain B in addition to A. To explore the effects of aggregate strain propensities when hSOD1 variants are coexpressed, we generated digenic hSOD1G85R/WT and hSOD1G85R/D90A mice. Coexpression of hSOD1WT considerably shortened the lifespan of hSOD1G85R mice to the extent expected from the neurotoxicities of the variants alone. In contrast, coexpression of hSOD1D90A had a minimal effect on survival, far smaller than expected. Moreover, time from onset to the end stage was markedly prolonged in the hSOD1G85R/D90A mice. Aggregation of hSOD1 developed concomitantly with motor neuron disease, and the aggregates contained large amounts of both coexpressed variants in both digenic models. Our findings suggest that hSOD1WT has high a capacity to coaggregate with mutants and enhance neurotoxicity. Such interactions may be restricted by differences in strain propensities, which may contribute to the primarily recessive inheritance associated with the hSOD1D90A mutation.
超氧化物歧化酶-1（SOD1）突变是肌萎缩侧索硬化症（ALS）的常见病因。通常呈显性遗传，但在最常见突变D90A的携带者中，纯合子个体以及更罕见的杂合子个体均可发病，且临床表现存在无法解释的差异。越来越多的证据表明，SOD1聚集体的朊病毒样传播是该疾病的主要病因。在ALS的人类SOD1（hSOD1）转基因小鼠模型中发现了两种不同的聚集体菌株。菌株A由包括hSOD1G85R和hSOD1WT在内的大多数突变体形成，而hSOD1D90A转基因小鼠除了形成菌株A外，还形成了独特的菌株B。为了探究hSOD1变体共表达时聚集体菌株倾向的影响，我们构建了双基因hSOD1G85R/WT和hSOD1G85R/D90A小鼠。hSOD1WT的共表达显著缩短了hSOD1G85R小鼠的寿命，缩短程度达到仅由变体的神经毒性所预期的程度。相比之下，hSOD1D90A的共表达对生存期的影响极小，远小于预期。此外，hSOD1G85R/D90A小鼠从发病到终末期的时间明显延长。hSOD1的聚集与运动神经元疾病同时发生，并且在两种双基因模型的聚集体中都含有大量共表达的变体。我们的研究结果表明，hSOD1WT与突变体共聚集并增强神经毒性的能力很强。这种相互作用可能受到菌株倾向差异的限制，这可能导致与hSOD1D90A突变相关的主要隐性遗传。
