Hashimoto Makoto, Hsu Leigh J, Rockenstein Edward, Takenouchi Takato, Mallory Margaret, Masliah Eliezer
Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, California 92093-0624, USA.
J Biol Chem. 2002 Mar 29;277(13):11465-72. doi: 10.1074/jbc.M111428200. Epub 2002 Jan 14.
The expression of alpha-synuclein, a synaptic molecule implicated in the pathogenesis of neurodegenerative disorders such as Parkinson's disease and Lewy body disease is increased upon injury to the nervous system, indicating that it might play a role in regeneration and plasticity; however, the mechanisms are unclear. Because c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase family, plays an important role in stress response, the main objective of the present study was to better understand the involvement of this pathway in the signaling responses associated with resistance to injury in cells expressing alpha-synuclein. For this purpose, the JNK-signaling pathway was investigated in alpha-synuclein-transfected neuronal cell line glucose transporter (GT) 1-7 under oxidative stress conditions. Although hydrogen peroxide challenge resulted in JNK activation and cell death in cells transfected with vector control or beta-synuclein, alpha-synuclein-transfected cells were resistant to hydrogen peroxide, and JNK was not activated. The inactivation of JNK in the alpha-synuclein-transfected cells was associated with increased expression and activity of JNK-interacting protein (JIP)-1b/islet-brain (IB)1, the scaffold protein for the JNK pathway. Similarly, cells transfected with JIP-1b/IB1 were resistant to hydrogen peroxide associated with inactivation of the JNK pathway. In these cells, expression of endogenous alpha-synuclein was significantly increased at the protein level. Furthermore, alpha-synuclein was co-localized with JIP-1b/IB1 in the growth cones. Taken together, these results suggest that increased alpha-synuclein expression might protect cells from oxidative stress by inactivation of JNK via increased expression of JIP-1b/IB1. Furthermore, interactions between alpha-synuclein and JIP-1b/IB1 may play a mutual role in the neuronal response to injury and neurodegeneration.
α-突触核蛋白是一种与帕金森病和路易体病等神经退行性疾病发病机制相关的突触分子，在神经系统损伤时其表达会增加，这表明它可能在再生和可塑性中发挥作用；然而，其机制尚不清楚。由于丝裂原活化蛋白激酶家族成员c-Jun氨基末端激酶（JNK）在应激反应中起重要作用，本研究的主要目的是更好地了解该通路在表达α-突触核蛋白的细胞中与抗损伤信号反应中的作用。为此，在氧化应激条件下，对转染了α-突触核蛋白的神经元细胞系葡萄糖转运体（GT）1-7中的JNK信号通路进行了研究。尽管过氧化氢刺激导致转染载体对照或β-突触核蛋白的细胞中JNK激活和细胞死亡，但转染α-突触核蛋白的细胞对过氧化氢具有抗性，且JNK未被激活。α-突触核蛋白转染细胞中JNK的失活与JNK相互作用蛋白（JIP）-1b/胰岛脑（IB）1（JNK通路的支架蛋白）的表达和活性增加有关。同样，转染JIP-1b/IB1的细胞对过氧化氢具有抗性，且与JNK通路失活有关。在这些细胞中，内源性α-突触核蛋白的蛋白水平显著增加。此外，α-突触核蛋白与JIP-1b/IB1在生长锥中共定位。综上所述，这些结果表明，α-突触核蛋白表达增加可能通过增加JIP-1b/IB1的表达使JNK失活，从而保护细胞免受氧化应激。此外，α-突触核蛋白与JIP-1b/IB1之间的相互作用可能在神经元对损伤和神经退行性变的反应中发挥相互作用。
