中国神经再生研究(英文版) ›› 2015, Vol. 10 ›› Issue (11): 1752-1753.doi: 10.4103/1673-5374.165295

• 观点:退行性病与再生 • 上一篇    下一篇

中脑多巴胺能系统中神经保护和再生潜能:Parkin和GDNF/ Ret信号的作用

  

  • 收稿日期:2015-07-15 出版日期:2015-12-07 发布日期:2015-12-07

The neuroprotective and regenerative potential of parkin and GDNF/Ret signaling in the midbrain dopaminergic system

Edgar R. Kramer*   

  1. Development and Maintenance of the Nervous System, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Received:2015-07-15 Online:2015-12-07 Published:2015-12-07
  • Contact: Edgar R. Kramer, Ph.D.,kramer@zmnh.uni-hamburg.de.
  • Supported by:

    I thank Julia Kuhl for help with the art work and together with Mahmoud Bassal for comments on the paper. We apologize to all authors whose work could not be cited here due to paper length restrictions.This study was partly supported by grants from the DFG (KR 3529/4-1 to ERK) and the town of Hamburg (Lexi to ERK).

摘要:

帕金森病是仅次于阿尔茨海默病的最常见神经退行性疾病。帕金森病的病因学目前还没有被完全理解,但其主要特征已有研究,即黑质致密部的纹状体多巴胺神经支配损失,路易体中的蛋白聚集以及神经突形态的多巴胺能退变等。除了α突触核蛋白在路易体和神经突起中的积累,遗传的突变基因,例如parkin,PINK,DJ-1,LRRK2蛋白质与遗传性帕金森病密切相关。目前,仅有症候性治疗方式适用于帕金森病,但却无法治愈。许多研究都在努力寻找神经营养等因素刺激黑质致密部的多巴胺神经元体现保护和再生的特性。加强Parkin和Ret信号相结合的办法可能被视为保护帕金森患者遗留下来的多巴胺神经元,甚至有助于刺激轴突多巴胺再生的方法。

Abstract:

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease. The etiology of PD is still not completely understood, but degeneration of dopaminergic (DA) neurons in substantia nigra pars compacta (SNpc), loss of DA innervation of the striatum, and protein aggregates in form of Lewy bodies and neurites are established hallmarks. Besides α-synuclein accumulation in Lewy bodies and neurites, also genetic mutations in the genes encoding for example parkin, PINK, DJ-1 and LRRK2 proteins have been associated with the inherited form of PD and an association study linked also the receptor tyrosine kinas Ret with PD. Currently there are only symptomatic treatments available for PD and no cure. Therefore many efforts are made to find neurotrophic and other factors to stimulate SNpc DA neuron protection and regeneration. Glial cell line-derived neurotrophic factor (GDNF) is the founding member of the GDNF family of ligands (GFLs) including neurturin, artemin and persephin which belong to the transforming growth factor-β (TGF-β) superfamily. GDNF bindings with high affinity to GDNF family receptor α1 (GFRα1) that can subsequent activate the receptor tyrosine kinase Ret or alternative GDNF receptors such as the neuronal cell adhesion molecule NCAM, integrins αV and βI, syndecan-3 or N-cadherin. The canonical GDNF receptor Ret signals through many pathways such as the PI3K/Akt, Ras/MAPK, NF-κB, JNK, and PLC?/PKC pathways, while NCAM  can activate Fyn and FAK. GDNF is thought to be the most potent neurotrophic factor for the two midbrain dopaminergic (DA) neuron populations, the SNpc DA neurons dying in PD patients and the ventral tegmental area (VTA) DA neurons altered during drug addiction. Surprisingly, although GDNF stimulates neuronal differentiation, neurite outgrowth, synapse formation, and dopamine release in cell culture, GDNF was shown to be dispensable for DA neuron development and maintenance. In contrast, we could show in two different DA system specific Ret knockout mice, that Ret is dispensable during development but important for maintaining SNpc DA neurons in aging mice.