Oh Sang-Min, Chang Mi-Yoon, Song Jae-Jin, Rhee Yong-Hee, Joe Eun-Hye, Lee Hyun-Seob, Yi Sang-Hoon, Lee Sang-Hun
Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea.
Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea.
EMBO Mol Med. 2015 May;7(5):510-25. doi: 10.15252/emmm.201404610.
Use of the physiological mechanisms promoting midbrain DA (mDA) neuron survival seems an appropriate option for developing treatments for Parkinson's disease (PD). mDA neurons are specifically marked by expression of the transcription factors Nurr1 and Foxa2. We show herein that Nurr1 and Foxa2 interact to protect mDA neurons against various toxic insults, but their expression is lost during aging and degenerative processes. In addition to their proposed cell-autonomous actions in mDA neurons, forced expression of these factors in neighboring glia synergistically protects degenerating mDA neurons in a paracrine mode. As a consequence of these bimodal actions, adeno-associated virus (AAV)-mediated gene delivery of Nurr1 and Foxa2 in a PD mouse model markedly protected mDA neurons and motor behaviors associated with nigrostriatal DA neurotransmission. The effects of the combined gene delivery were dramatic, highly reproducible, and sustained for at least 1 year, suggesting that expression of these factors is a promising approach in PD therapy.
利用促进中脑多巴胺（mDA）神经元存活的生理机制似乎是开发帕金森病（PD）治疗方法的一个合适选择。mDA神经元通过转录因子Nurr1和Foxa2的表达而被特异性标记。我们在此表明，Nurr1和Foxa2相互作用以保护mDA神经元免受各种毒性损伤，但其表达在衰老和退行性过程中会丧失。除了它们在mDA神经元中所提出的细胞自主作用外，在邻近胶质细胞中强制表达这些因子会以旁分泌模式协同保护退化的mDA神经元。由于这些双峰作用，在PD小鼠模型中，腺相关病毒（AAV）介导的Nurr1和Foxa2基因递送显著保护了mDA神经元以及与黑质纹状体DA神经传递相关的运动行为。联合基因递送的效果显著、高度可重复且至少持续1年，这表明这些因子的表达是PD治疗中一种有前景的方法。
