内源性逆转录病毒糖蛋白(syncytin)在骨骼肌高表达导致逆行性运动神经元损伤和运动功能受损的机制

More and more evidences suggest "distal axonopathy " hypothesis in Motor Neuron Disease (MND). Motor unit loss and associated muscle dysfunction precedes motor neuron death in accordance with this hypothesis. We previously reported the aberrant expression of human endogenous retroviruse ERVWE1 env, which encodes protein syncytin, in the atrophied muscles of patients suffered from MND. We further observed the motor dysfunction induced by the elevated level of syncytin in anterior tibial muscle of mice, and that the expression of syncytin in gastrocnemius was not affected in the mice with sciatic nerve injury. These suggest that the aberrant expression of syncytin in the atrophied muscles of MND may be involved in the pathogenesis of motor neuron degeneration rather than the consequences of neuronal degeneration. In this project, mice will be muscular injected with syncytin expression vector. In order to better understand the mechanisms of motor dysfunction induced by elevated syncytin in skeletal muscles, we will take a systematic pathological study of the endplates, axons, ventral nerve roots and motor neurons at multiple time points. Furthermore, the mechanisms inducing above impairment will be explored. The imbalance between the neuroprotective factors VEGF, IGF, TGFβ, and the cytotoxic factors IL-6, TNFα induced by elevated syncytin will be studied in vivo and in vitro. We will explore the inhibitory effects of syncytin on neutral amino acid transporter ASCT1 and the pathogenic effects of such inhibition to distal axons. The mRNA levels of transcriptional factors GCM1, SP1, GATA-2, GATA-3, and AP2 will be detected in the atrophied muscles of patients with MND. The transcriptional modulaton of these transcriptional factors on syncytin in skeletal muscles will also be studied. This project will enrich the contents in finding the association between MND and active endogenous retroviruses, and will also provide helpful evidences for the early neuroprotective treatment of MND.

越来越多证据支持运动神经元病是末梢轴突病的假说，即疾病起源于骨骼肌继而发生逆行性运动神经元变性。我们在国际上首次报道了人内源性逆转录病毒膜蛋白syncytin在运动神经元病病人萎缩肌肉组织中异常表达，继而发现小鼠胫前肌syncytin的异常表达损伤动物运动功能，但机制不清。本课题应用骨骼肌在体植入syncytin表达载体小鼠，探讨syncytin对运动终板、轴突和/或逆行性脊髓腹侧神经根和运动神经元的损伤作用；探讨syncytin通过影响神经保护因子VEGF 、IGF 、TGFβ和细胞毒性因子IL-6、TNFα的表达，并抑制氨基酸转运体ASCT1影响兴奋毒性氨基酸代谢，导致末梢轴突损伤的机制；探讨转录因子调控syncytin在运动神经元病骨骼肌异常转录的机制。本课题将为运动神经元病与活化的内源性逆转录病毒的研究丰富新内容，为运动神经元病早期神经保护治疗提供新的理论依据。

越来越多证据支持运动神经元病是末梢轴突病的假说，即疾病起源于骨骼肌继而发生逆行性运动神经元变性。我们在国际上首次报道了人内源性逆转录病毒膜蛋白syncytin 1在运动神经元病病人萎缩肌肉组织中异常表达，继而发现小鼠胫前肌syncytin的异常表达损伤动物运动功能，但机制不清。本项目应用骨骼肌在体植入表达syncytin 1的病毒载体小鼠，研究结果显示syncytin 1异常高表达会逆行性引起脊髓前角运动神经元变性、缺失，激活星形胶质细胞和小胶质细胞，骨骼肌呈现神经源性损伤。应用动物模型和细胞模型研究，均证实syncytin 1可以通过抑制氨基酸转运体ASCT1，致使氨基酸蓄积，进而引起兴奋性氨基酸的毒性作用。syncytin 1介导炎症级联反应，引起炎症因子TNF-α表达水平升高和神经保护性因子VEGF的升高，但是其神经保护作用不足以避免运动神经元损伤的发生。MND病人肌肉组织中syncytin 1转录因子GCM1、GATA-3的异常表达，并不足以调控syncytin 1在MND骨骼肌异常转录。本课题为MND与活化的内源性逆转录病毒基因之间的关系丰富了新内容，为MND的“dying back”假说提供了新的证据，但MND病人骨骼肌syncytin 1的异常转录调控机制仍然值得深入探讨。

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