Antagonizing bone morphogenetic protein 4 attenuates disease progression in a rat model of amyotrophic lateral sclerosis
Antagonizing bone morphogenetic protein 4 attenuates disease progression in a rat model of amyotrophic lateral sclerosis
复制标题
DOI：
10.1016/j.expneurol.2018.06.009
复制
发表时间：
2018-09
影响因子：
5.3
通讯作者：
T. Shijo;H. Warita;N. Suzuki;Kensuke Ikeda;S. Mitsuzawa;T. Akiyama;H. Ono;A. Nishiyama;R. Izumi;Y. Kitajima;M. Aoki
中科院分区：
文献类型：
--
作者：
T. Shijo;H. Warita;N. Suzuki;Kensuke Ikeda;S. Mitsuzawa;T. Akiyama;H. Ono;A. Nishiyama;R. Izumi;Y. Kitajima;M. Aoki
肌萎缩性侧索硬化症（ALS）是一种成人发病的致死性神经退行性综合征，其特征是运动神经元的全身性丧失，脊髓和大脑中有明显的星形细胞增生和小胶质细胞增生。星形胶质细胞在维持运动神经元周围的细胞外微环境中起着至关重要的作用，并被各种损伤激活。越来越多的证据表明，在神经退行性疾病（包括ALS）患者中，慢性和持续的星形细胞激活引起的非细胞自主神经毒性。然而，星形细胞增多症对ALS患者有害影响的机制仍未得到解决。我们关注骨形态发生蛋白作为促进成人脊髓星形细胞发生及其激活的主要可溶性因子。在als相关突变Cu/Zn超氧化物歧化酶基因转基因大鼠模型中，BMP4在脊髓腹角反应性星形胶质细胞中逐渐上调，而BMP4拮抗剂noggin在神经元变性过程中降低。发病后持续鞘内补充脑蛋白可显著改善有症状的ALS模型大鼠的运动功能障碍症状、神经源性肌肉萎缩，并延长生存期，尽管对神经元死亡本身缺乏威慑作用。外源性noggin通过灭活Smad1/5/8和p38丝裂原激活的蛋白激酶途径，抑制星形细胞肥大、星形细胞发生和神经炎症。此外，鞘内输注abmp4靶向反义寡核苷酸，并在体内选择性地敲低bmp4，从而抑制星形胶质细胞和小胶质细胞的激活，再现了noggin治疗的上述结果。总的来说，我们阐明了BMP4参与过度胶质瘤的过程，加剧了ALS模型大鼠的疾病进展。我们的研究表明，BMP4及其下游信号可能是ALS疾病改善治疗的新靶点。
Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal neurodegenerative syndrome characterized by the systemic loss of motor neurons with prominent astrocytosis and microgliosis in the spinal cord and brain. Astrocytes play an essential role in maintaining extracellular microenvironments that surround motor neurons, and are activated by various insults. Growing evidence points to a non-cell autonomous neurotoxicity caused by chronic and sustained astrocytic activation in patients with neurodegenerative diseases, including ALS. However, the mechanisms that underlie the harmful effects of astrocytosis in patients with ALS remain unresolved. We focused on bone morphogenetic proteins as a major soluble factor that promotes astrocytogenesis and its activation in the adult spinal cord. In a transgenic rat model with ALS-linked mutant Cu/Zn superoxide dismutase gene, BMP4 was progressively up-regulated in reactive astrocytes of the spinal ventral horns, whereas the BMP-antagonist noggin was decreased in association with neuronal degeneration. Continuous intrathecal noggin supplementation after disease onset significantly ameliorated motor dysfunction symptoms, neurogenic muscle atrophy, and extended survival of symptomatic ALS model rats, despite lack of deterrence against neuronal death itself. The exogenous noggin inhibited astrocytic hypertrophy, astrocytogenesis, and neuroinflammation by inactivating both Smad1/5/8 and p38 mitogen-activated protein kinase pathways. Moreover, intrathecal infusion of aBmp4-targeted antisense oligonucleotides and provided selectiveBmp4knockdown in vivo, which suppressed astrocyte and microglia activation, reproducing the aforementioned results by noggin treatment. Collectively, we clarified the involvement of BMP4 in the processes of excessive gliosis that exacerbate the disease progression of the ALS model rats. Our study demonstrated that BMP4, with its downstream signaling, might be a novel therapeutic target for disease-modifying therapies in ALS.