Peters Sebastian, Zitzelsperger Eva, Kuespert Sabrina, Iberl Sabine, Heydn Rosmarie, Johannesen Siw, Petri Susanne, Aigner Ludwig, Thal Dietmar R, Hermann Andreas, Weishaupt Jochen H, Bruun Tim-Henrik, Bogdahn Ulrich
Department of Neurology, University Hospital Regensburg, Regensburg, Germany.
Department of Hematology, University Hospital Regensburg, Regensburg, Germany.
Front Neurol. 2017 Dec 15;8:669. doi: 10.3389/fneur.2017.00669. eCollection 2017.
Amyotrophic lateral sclerosis (ALS) represents a fatal orphan disease with high unmet medical need, and a life time risk of approx. 1/400 persons per population. Based on increasing knowledge on pathophysiology including genetic and molecular changes, epigenetics, and immune dysfunction, inflammatory as well as fibrotic processes may contribute to the heterogeneity and dynamics of ALS. Animal and human studies indicate dysregulations of the TGF-β system as a common feature of neurodegenerative disorders in general and ALS in particular. The TGF-β system is involved in different essential developmental and physiological processes and regulates immunity and fibrosis, both affecting neurogenesis and neurodegeneration. Therefore, it has emerged as a potential therapeutic target for ALS: a persistent altered TGF-β system might promote disease progression by inducing an imbalance of neurogenesis and neurodegeneration. The current study assessed the activation state of the TGF-β system within the periphery/in life disease stage (serum samples) and a late stage of disease (central nervous system tissue samples), and a potential influence upon neuronal stem cell (NSC) activity, immune activation, and fibrosis. An upregulated TGF-β system was suggested with significantly increased TGF-β1 protein serum levels, enhanced TGF-β2 mRNA and protein levels, and a strong trend toward an increased TGF-β1 protein expression within the spinal cord (SC). Stem cell activity appeared diminished, reflected by reduced mRNA expression of NSC markers Musashi-1 and Nestin within SC-paralleled by enhanced protein contents of Musashi-1. Doublecortin mRNA and protein expression was reduced, suggesting an arrested neurogenesis at late stage ALS. Chemokine/cytokine analyses suggest a shift from a neuroprotective toward a more neurotoxic immune response: anti-inflammatory chemokines/cytokines were unchanged or reduced, expression of proinflammatory chemokines/cytokines were enhanced in ALS sera and SC postmortem tissue. Finally, we observed upregulated mRNA and protein expression for fibronectin in motor cortex of ALS patients which might suggest increased fibrotic changes. These data suggest that there is an upregulated TGF-β system in specific tissues in ALS that might lead to a "neurotoxic" immune response, promoting disease progression and neurodegeneration. The TGF-β system therefore may represent a promising target in treatment of ALS patients.
肌萎缩侧索硬化症（ALS）是一种致命的罕见病，存在大量未被满足的医疗需求，人群中终身患病风险约为1/400。基于对包括基因和分子变化、表观遗传学及免疫功能障碍在内的病理生理学的认识不断增加，炎症以及纤维化过程可能导致了ALS的异质性和动态变化。动物和人体研究表明，转化生长因子-β（TGF-β）系统失调是一般神经退行性疾病尤其是ALS的共同特征。TGF-β系统参与不同的重要发育和生理过程，并调节免疫和纤维化，这两者都会影响神经发生和神经退行性变。因此，它已成为ALS的一个潜在治疗靶点：持续改变的TGF-β系统可能通过诱导神经发生和神经退行性变失衡来促进疾病进展。本研究评估了外周/疾病生命期阶段（血清样本）和疾病晚期（中枢神经系统组织样本）TGF-β系统的激活状态，以及对神经干细胞（NSC）活性、免疫激活和纤维化的潜在影响。研究提示TGF-β系统上调，表现为血清中TGF-β1蛋白水平显著升高、TGF-β2 mRNA和蛋白水平增强，并且脊髓中TGF-β1蛋白表达有强烈的升高趋势。干细胞活性似乎降低，表现为脊髓内NSC标志物Musashi-1和巢蛋白的mRNA表达减少，同时Musashi-1的蛋白含量增加。双皮质素mRNA和蛋白表达降低，提示ALS晚期神经发生停滞。趋化因子/细胞因子分析表明免疫反应从神经保护向更具神经毒性转变：抗炎趋化因子/细胞因子未改变或减少，促炎趋化因子/细胞因子在ALS血清和死后脊髓组织中的表达增强。最后，我们观察到ALS患者运动皮层中纤连蛋白的mRNA和蛋白表达上调，这可能提示纤维化改变增加。这些数据表明，ALS特定组织中TGF-β系统上调可能导致“神经毒性”免疫反应，促进疾病进展和神经退行性变。因此，TGF-β系统可能是治疗ALS患者的一个有前景的靶点。
