中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2016, Vol. 11 ›› Issue (8): 1201-1203.doi: 10.4103/1673-5374.189160

• 综述:神经损伤修复保护与再生 • 上一篇    下一篇

选择性神经元磷酸酶和张力同源基因缺失：对轴突再生能够放松生长刹车又不失控吗？

  

  • 出版日期:2016-08-31 发布日期:2016-08-31
  • 基金资助:

    研究由NS073857致O.S.，5T32GM008620致E.G.，以及治疗医学、治愈研究和个人捐助者慷慨捐赠支持。

Selective neuronal PTEN deletion: can we take the brakes off of growth without losing control?

Erin A. Gutilla1, 2, Oswald Steward1, 2, 3, 4, 5, *   

  1. 1 Reeve-Irvine Research Center, University of California Irvine School of Medicine, Irvine, CA, USA 2 Department of Anatomy & Neurobiology, University of California Irvine School of Medicine, Irvine, CA, USA 3 Department of Neurobiology & Behavior, University of California Irvine School of Medicine, Irvine, CA, USA 4 Department of Neurosurgery, University of California Irvine School of Medicine, Irvine, CA, USA 5 Center for the Neurobiology of Learning and Memory, University of California Irvine School of Medicine, Irvine, CA, USA
  • Online:2016-08-31 Published:2016-08-31
  • Contact: Oswald Steward, Ph.D., osteward@uci.edu.
  • Supported by:

    This work was supported by NS073857 to OS, 5T32GM008620 to EG and generous donations from Cure Medical, Research for Cure, and individual donors.

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摘要：

损伤或不健康的轴突再生给大部分神经系统疾病带来了治疗前景，包括急性脑或脊髓创伤，脑卒中和神经变性疾病。磷酸酶和张力同源基因（PTEN）已成为轴突再生的重要调节剂，最近多个研究团队的研究结果也证明了PTEN作为治疗靶的潜力。文章报道了长期缺失PTEN，一种肿瘤抑制基因，不会导致任何重大的可检测的病理病变，并且还可以增强神经元活性。在年轻小鼠运动皮质中进行PTEN选择性删除，他们使用已被用于促进脊髓损伤后皮质脊髓束再生相同的方法特别评估了PTEN丢失的影响。文章中主要阐述的是有没有可能在不失控的情况下放松对这一如此强大的促生长途径的控制？在评估这种潜在风险的第一步骤中，Oswald Steward教授采用了与他们过往研究脊髓损伤CST再生的相同实验模型。但现在的研究还不能作为临床前治疗的开发需要，因为研究并不完全安全，在PTEN删除后小鼠存活长达18个月并无任何不良影响（早期老年小鼠）。而其他涉及数百个PTEN缺失小鼠和大鼠的感觉运动皮层再生增强的研究同样表明其能改善脊髓损伤后的运动功能，并没有出现过负作用。总之，结合以前的报告的研究结果，在不触发不良反应的前提下靶向PTEN是有治疗可能性的。

orcid: 0000-0002-8466-9902 (Erin A. Gutilla), 0000-0001-7069-8756 (Oswald Steward) 

Abstract:

The limited ability for injured adult axons to regenerate is a major cause for limited functional recovery after injury to the nervous system, motivating numerous efforts to uncover mechanisms capable of enhancing regeneration potential. One promising strategy involves deletion or knockdown of the phosphatase and tensin (PTEN) gene. Conditional genetic deletion of PTEN before, immediately following, or several months after spinal cord injury enables neurons of the corticospinal tract (CST) to regenerate their axons across the lesion, which is accompanied by enhanced recovery of skilled voluntary motor functions mediated by the CST. Although conditional genetic deletion or knockdown of PTEN in neurons enables axon regeneration, PTEN is a well-known tumor suppressor and mutations of the PTEN gene disrupt brain development leading to neurological abnormalities including macrocephaly, seizures, and early mortality. The long-term consequences of manipulating PTEN in the adult nervous system, as would be done for therapeutic intervention after injury, are only now being explored. Here, we summarize evidence indicating that long-term deletion of PTEN in mature neurons does not cause evident pathology; indeed, cortical neurons that have lived without PTEN for over 1 year appear robust and healthy. Studies to date provide only a frst look at potential negative consequences of PTEN deletion or knockdown, but the absence of any detectable neuropathology supports guarded optimism that interventions to enable axon regeneration after injury are achievable.

Key words: PTEN, mTOR, spinal cord injury, corticospinal tract, motor system, axon regeneration, recovery of function