Department of Neuroscience Rita Levi Montalcini, University of Turin, via Cherasco 15, 10126 Turin, Italy
Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, Regione Gonzole 10, 10043 Orbassano, Turin, Italy.
Dis Model Mech. 2020 May 15;13(5):dmm043513. doi: 10.1242/dmm.043513.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both lower and upper motor neurons (MNs) in the central nervous system. ALS etiology is highly multifactorial and multifarious, and an effective treatment is still lacking. Neuroinflammation is a hallmark of ALS and could be targeted to develop new therapeutic approaches. Interestingly, the transcription factor Nurr1 has been demonstrated to have an important role in the inflammatory process in several neurological disorders, such as Parkinson's disease and multiple sclerosis. In the present paper, we demonstrate for the first time that Nurr1 expression levels are upregulated in the peripheral blood of ALS patients. Moreover, we investigated Nurr1 function in the SOD1-G93A mouse model of ALS. Nurr1 was strongly upregulated in the spinal cord during the asymptomatic and early symptomatic phases of the disease, where it promoted the expression of brain-derived neurotrophic factor mRNA and the repression of NFκB pro-inflammatory targets, such as inducible nitric oxide synthase. Therefore, we hypothesize that Nurr1 is activated in an early phase of the disease as a protective endogenous anti-inflammatory mechanism, although not sufficient to reverse disease progression. On the basis of these observations, Nurr1 could represent a potential biomarker for ALS and a promising target for future therapies.
肌萎缩侧索硬化症（ALS）是一种影响中枢神经系统中上下运动神经元（MNs）的神经退行性疾病。ALS 的病因高度复杂多样，目前仍缺乏有效的治疗方法。神经炎症是 ALS 的一个标志特征，可作为开发新治疗方法的靶点。有趣的是，转录因子 Nurr1 已被证明在几种神经退行性疾病（如帕金森病和多发性硬化症）的炎症过程中具有重要作用。在本文中，我们首次证明 Nurr1 的表达水平在 ALS 患者的外周血中上调。此外，我们还研究了 Nurr1 在 SOD1-G93A ALS 小鼠模型中的功能。Nurr1 在疾病无症状和早期症状阶段强烈上调，在该阶段，它促进脑源性神经营养因子 mRNA 的表达并抑制 NFκB 促炎靶标，如诱导型一氧化氮合酶。因此，我们假设 Nurr1 在疾病的早期阶段被激活，作为一种保护性的内源性抗炎机制，尽管不足以逆转疾病进展。基于这些观察结果，Nurr1 可能成为 ALS 的潜在生物标志物和未来治疗的有希望的靶点。
