Pasetto Laura, Pozzi Silvia, Castelnovo Mariachiara, Basso Manuela, Estevez Alvaro G, Fumagalli Stefano, De Simoni Maria Grazia, Castellaneta Valeria, Bigini Paolo, Restelli Elena, Chiesa Roberto, Trojsi Francesca, Monsurrò Maria Rosaria, Callea Leonardo, Malešević Miroslav, Fischer Gunter, Freschi Mattia, Tortarolo Massimo, Bendotti Caterina, Bonetto Valentina
Department of Molecular Biochemistry and Pharmacology.
Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy.
J Neurosci. 2017 Feb 8;37(6):1413-1427. doi: 10.1523/JNEUROSCI.2462-16.2016. Epub 2016 Dec 23.
Neuroinflammation is a major hallmark of amyotrophic lateral sclerosis (ALS), which is currently untreatable. Several anti-inflammatory compounds have been evaluated in patients and in animal models of ALS, but have been proven disappointing in part because effective targets have not yet been identified. Cyclophilin A, also known as peptidylprolyl cis-/trans-isomerase A (PPIA), as a foldase is beneficial intracellularly, but extracellularly has detrimental functions. We found that extracellular PPIA is a mediator of neuroinflammation in ALS. It is a major inducer of matrix metalloproteinase 9 and is selectively toxic for motor neurons. High levels of PPIA were found in the CSF of SOD1 mice and rats and sporadic ALS patients, suggesting that our findings may be relevant for familial and sporadic cases. A specific inhibitor of extracellular PPIA, MM218, given at symptom onset, rescued motor neurons and extended survival in the SOD1 mouse model of familial ALS by 11 d. The treatment resulted in the polarization of glia toward a prohealing phenotype associated with reduced NF-κB activation, proinflammatory markers, endoplasmic reticulum stress, and insoluble phosphorylated TDP-43. Our results indicates that extracellular PPIA is a promising druggable target for ALS and support further studies to develop a therapy to arrest or slow the progression of the disease in patients. We provide evidence that extracellular cyclophilin A, also known as peptidylprolyl cis-/trans-isomerase A (PPIA), is a mediator of the neuroinflammatory reaction in amyotrophic lateral sclerosis (ALS) and is toxic for motor neurons. Supporting this, a specific extracellular PPIA inhibitor reduced neuroinflammation, rescued motor neurons, and extended survival in the SOD1 mouse model of familial ALS. Our findings suggest selective pharmacological inhibition of extracellular PPIA as a novel therapeutic strategy, not only for SOD1-linked ALS, but possibly also for sporadic ALS. This approach aims to address the neuroinflammatory reaction that is a major hallmark of ALS. However, given the complexity of the disease, a combination of therapeutic approaches may be necessary.
神经炎症是肌萎缩侧索硬化症（ALS）的一个主要标志，目前尚无治疗方法。几种抗炎化合物已在ALS患者和动物模型中进行了评估，但结果令人失望，部分原因是尚未确定有效的靶点。亲环素A，也称为肽基脯氨酰顺/反异构酶A（PPIA），作为一种折叠酶在细胞内有益，但在细胞外具有有害功能。我们发现细胞外PPIA是ALS神经炎症的介质。它是基质金属蛋白酶9的主要诱导剂，对运动神经元具有选择性毒性。在SOD1小鼠、大鼠和散发性ALS患者的脑脊液中发现了高水平的PPIA，这表明我们的发现可能与家族性和散发性病例相关。在症状出现时给予细胞外PPIA的特异性抑制剂MM218，可挽救运动神经元，并使家族性ALS的SOD1小鼠模型的生存期延长11天。该治疗导致胶质细胞向与NF-κB激活减少、促炎标志物、内质网应激和不溶性磷酸化TDP-43相关的促愈合表型极化。我们的结果表明，细胞外PPIA是ALS一个有前景的可成药靶点，并支持进一步研究以开发一种疗法来阻止或减缓患者疾病的进展。我们提供的证据表明，细胞外亲环素A，也称为肽基脯氨酰顺/反异构酶A（PPIA），是肌萎缩侧索硬化症（ALS）神经炎症反应的介质，对运动神经元有毒性。支持这一点的是，一种特异性细胞外PPIA抑制剂可减少神经炎症，挽救运动神经元，并延长家族性ALS的SOD1小鼠模型的生存期。我们的发现表明，选择性药理抑制细胞外PPIA作为一种新的治疗策略，不仅适用于与SOD1相关的ALS，也可能适用于散发性ALS。这种方法旨在解决作为ALS主要标志的神经炎症反应。然而，鉴于该疾病的复杂性，可能需要多种治疗方法的组合。
