Brambilla Liliana, Guidotti Giulia, Martorana Francesca, Iyer Anand M, Aronica Eleonora, Valori Chiara F, Rossi Daniela
Laboratory for Research on Neurodegenerative Disorders, IRCCS Fondazione Salvatore Maugeri, 27100 Pavia, Italy.
Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Hum Mol Genet. 2016 Jul 15;25(14):3080-3095. doi: 10.1093/hmg/ddw161. Epub 2016 Jun 10.
Considerable evidence indicates that neurodegeneration in amyotrophic lateral sclerosis (ALS) can be conditioned by a deleterious interplay between motor neurons and astrocytes. Astrocytes are the major glial component in the central nervous system (CNS) and fulfill several activities that are essential to preserve CNS homeostasis. In physiological and pathological conditions, astrocytes secrete a wide range of factors by which they exert multimodal influences on their cellular neighbours. Among others, astrocytes can secrete glial cell line-derived neurotrophic factor (GDNF), one of the most potent protective agents for motor neurons. This suggests that the modulation of the endogenous mechanisms that control the production of astrocytic GDNF may have therapeutic implications in motor neuron diseases, particularly ALS. In this study, we identified TNF receptor 1 (TNFR1) signalling as a major promoter of GDNF synthesis/release from human and mouse spinal cord astrocytes in vitro and in vivo To determine whether endogenously produced TNFα can also trigger the synthesis of GDNF in the nervous system, we then focused on SOD1 ALS transgenic mice, whose affected tissues spontaneously exhibit high levels of TNFα and its receptor 1 at the onset and symptomatic stage of the disease. In SOD1 spinal cords, we verified a strict correlation in the expression of the TNFα, TNFR1 and GDNF triad at different stages of disease progression. Yet, ablation of TNFR1 completely abolished GDNF rises in both SOD1 astrocytes and spinal cords, a condition that accelerated motor neuron degeneration and disease progression. Our data suggest that the astrocytic TNFR1-GDNF axis represents a novel target for therapeutic intervention in ALS.
大量证据表明，肌萎缩侧索硬化症（ALS）中的神经退行性变可能受到运动神经元与星形胶质细胞之间有害相互作用的影响。星形胶质细胞是中枢神经系统（CNS）中的主要胶质成分，履行着维持CNS稳态所必需的多种功能。在生理和病理条件下，星形胶质细胞分泌多种因子，通过这些因子对其相邻细胞产生多模式影响。其中，星形胶质细胞可分泌胶质细胞系衍生神经营养因子（GDNF），它是对运动神经元最有效的保护因子之一。这表明，调控控制星形胶质细胞源性GDNF产生的内源性机制可能对运动神经元疾病，尤其是ALS具有治疗意义。在本研究中，我们确定肿瘤坏死因子受体1（TNFR1）信号传导是体外和体内人及小鼠脊髓星形胶质细胞中GDNF合成/释放的主要促进因子。为了确定内源性产生的TNFα是否也能在神经系统中触发GDNF的合成，我们随后聚焦于SOD1 ALS转基因小鼠，其受影响的组织在疾病发作和症状期自发地表现出高水平的TNFα及其受体1。在SOD1脊髓中，我们验证了在疾病进展的不同阶段TNFα、TNFR1和GDNF三者表达之间存在严格的相关性。然而，TNFR1的缺失完全消除了SOD1星形胶质细胞和脊髓中GDNF的升高，这种情况加速了运动神经元的退化和疾病进展。我们的数据表明，星形胶质细胞的TNFR1 - GDNF轴代表了ALS治疗干预的一个新靶点。
