UMR iBrain, Université de Tours, Inserm, 37000 Tours, France.
UTTIL, CHRU de Tours, 37000 Tours, France.
Int J Mol Sci. 2021 Feb 11;22(4):1796. doi: 10.3390/ijms22041796.
Protein aggregates in affected motor neurons are a hallmark of amyotrophic lateral sclerosis (ALS), but the molecular pathways leading to their formation remain incompletely understood. Oxidative stress associated with age, the major risk factor in ALS, contributes to this neurodegeneration in ALS. We show that several genes coding for enzymes of the ubiquitin and small ubiquitin-related modifier (SUMO) pathways exhibit altered expression in motor neuronal cells exposed to oxidative stress, such as the CCNF gene mutated in ALS patients. Eleven of these genes were further studied in conditions combining oxidative stress and the expression of an ALS related mutant of the superoxide dismutase 1 (SOD1) gene. We observed a combined effect of these two environmental and genetic factors on the expression of genes, such as Uhrf2, Rbx1, Kdm2b, Ube2d2, Xaf1, and Senp1. Overall, we identified dysregulations in the expression of enzymes of the ubiquitin and SUMO pathways that may be of interest to better understand the pathophysiology of ALS and to protect motor neurons from oxidative stress and genetic alterations.
受影响的运动神经元中的蛋白质聚集体是肌萎缩侧索硬化症 (ALS) 的一个标志，但导致其形成的分子途径仍不完全清楚。与年龄相关的氧化应激是 ALS 的主要风险因素，它促成了 ALS 中的神经退行性变。我们表明，几种编码泛素和小泛素相关修饰物 (SUMO) 途径的酶的基因在暴露于氧化应激的运动神经元细胞中表现出改变的表达，例如在 ALS 患者中突变的 CCNF 基因。这 11 个基因在结合氧化应激和超氧化物歧化酶 1 (SOD1) 基因的 ALS 相关突变体表达的条件下进一步研究。我们观察到这两个环境和遗传因素对基因表达的综合影响，如 Uhrf2、Rbx1、Kdm2b、Ube2d2、Xaf1 和 Senp1。总的来说，我们发现泛素和 SUMO 途径的酶的表达失调，这可能有助于更好地理解 ALS 的病理生理学，并保护运动神经元免受氧化应激和遗传改变的影响。
