中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (1): 38-44.doi: 10.4103/1673-5374.314290

• 综述:退行性病与再生 • 上一篇    下一篇

生长分化因子5：在帕金森病中具有神经保护潜力的神经营养因子

  

  • 出版日期:2022-01-05 发布日期:2021-09-18

Growth differentiation factor 5: a neurotrophic factor with neuroprotective potential in Parkinson’s disease

Susan R. Goulding1, Jayanth Anantha1, Louise M. Collins1, 2, Aideen M. Sullivan1, *, Gerard W. O’Keeffe1, *#br#   

  1. 1Department of Anatomy and Neuroscience, and Cork Neuroscience Centre, University College Cork, Cork, Ireland; 2Department of Physiology, University College Cork, Cork, Ireland
  • Online:2022-01-05 Published:2021-09-18
  • Contact: Gerard W. O’Keeffe, PhD, g.okeeffe@ucc.ie; Aideen M. Sullivan, PhD, a.sullivan@ucc.ie.

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摘要：

Neural Regen Res：生长分化因子5作为中脑多巴胺能神经元神经营养因子治疗帕金森病的潜在用途

   帕金森病是世界上最常见的运动障碍，影响超过600万人。它是一种与年龄有关的疾病，60岁以上的人中有1%患此病，80岁以上的人中有3%患此病。该病的特点是中脑黑质多巴胺能神经元及其分布于纹状体的轴突逐渐丧失，导致帕金森病特有的运动和非运动症状。这与中枢神经系统多个区域内α-突触核蛋白的细胞内积累是平行的。目前的治疗仅仅是对症的，不能阻止或延缓疾病的进展。阻止多巴胺能神经元丢失的一个有希望的疾病修饰策略是将神经营养因子靶向传递到黑质或纹状体，以保护黑质纹状体通路中残存的多巴胺能神经元。然而，两个成熟的神经营养因子，胶质细胞源性神经营养因子和neurturin的临床试验未能达到如上目的。这种失败被认为至少部分是由于Ret的α-突触核蛋白的下调，Ret是胶质细胞源性神经营养因子和neurturin的共同受体。生长分化因子5是神经营养因子骨形态发生蛋白家族的一员，通过Ret非依赖的经典Smad信号传导途径传递信号。

    来自爱尔兰科克大学学院的Gerard W. O’Keeffe团队认为生长分化因子5在大鼠脑中从早期发育到成年都有表达，与多巴胺能神经元的产生以及黑质纹状体通路的成熟和维持相一致。用重组人生长分化因子5蛋白、生长分化因子5过表达细胞或腺相关病毒诱导的生长分化因子5过表达治疗帕金森病动物模型已被证明对黑质纹状体多巴胺能通路的完整性具有有效的保护作用，并改善行为缺陷。因此在黑质纹状体系统变性后的α-突触核蛋白动物模型中，评价生长分化因子5是否具有神经保护作用具有重要意义。

文章在《中国神经再生研究（英文版）》杂志2022年 1 月 1 期发表。

https://orcid.org/0000-0001-5149-0933 (Gerard W. O’Keeffe); https://orcid.org/0000-0001-9692-6438 (Aideen M. Sullivan)

Abstract: Parkinson’s disease is the most common movement disorder worldwide, affecting over 6 million people. It is an age-related disease, occurring in 1% of people over the age of 60, and 3% of the population over 80 years. The disease is characterized by the progressive loss of midbrain dopaminergic neurons from the substantia nigra, and their axons, which innervate the striatum, resulting in the characteristic motor and non-motor symptoms of Parkinson’s disease. This is paralleled by the intracellular accumulation of α-synuclein in several regions of the nervous system. Current therapies are solely symptomatic and do not stop or slow disease progression. One promising disease-modifying strategy to arrest the loss of dopaminergic neurons is the targeted delivery of neurotrophic factors to the substantia nigra or striatum, to protect the remaining dopaminergic neurons of the nigrostriatal pathway. However, clinical trials of two well-established neurotrophic factors, glial cell line-derived neurotrophic factor and neurturin, have failed to meet their primary end-points. This failure is thought to be at least partly due to the downregulation by α-synuclein of Ret, the common co-receptor of glial cell line-derived neurorophic factor and neurturin. Growth/differentiation factor 5 is a member of the bone morphogenetic protein family of neurotrophic factors, that signals through the Ret-independent canonical Smad signaling pathway. Here, we review the evidence for the neurotrophic potential of growth/differentiation factor 5 in in vitro and in vivo models of Parkinson’s disease. We discuss new work on growth/differentiation factor 5’s mechanisms of action, as well as data showing that viral delivery of growth/differentiation factor 5 to the substantia nigra is neuroprotective in the α-synuclein rat model of Parkinson’s disease. These data highlight the potential for growth/differentiation factor 5 as a disease-modifying therapy for Parkinson’s disease. 

Key words: adeno-associated virus, bone morphogenetic protein, dopaminergic neurons, growth/differentiation factor 5, neurodegeneration, neuroprotection, neurotrophic factor, Parkinson’s disease, Smad signaling, α-synuclein