Stagi Massimiliano, Gorlovoy Philipp, Larionov Sergey, Takahashi Kazuya, Neumann Harald
Neural Regeneration Unit, Institute of Reconstructive Neurobiology, University Bonn Life and Brain Center, University Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
FASEB J. 2006 Dec;20(14):2573-5. doi: 10.1096/fj.06-6679fje. Epub 2006 Oct 26.
Axonal transport of mitochondria and synaptic vesicle precursors via kinesin motor proteins is essential to keep integrity of axons and synapses. Disturbance of axonal transport is an early sign of neuroinflammatory and neurodegenerative diseases. Treatment of cultured neurons by the inflammatory cytokine tumor necrosis factor-alpha (TNF) stimulated phosphorylation of c-Jun N-terminal kinase (JNK) in neurites. TNF treatment induced dissociation of the heavy chain kinesin family-5B (KIF5B) protein from tubulin in axons but not cell bodies as determined by lifetime-based Förster resonance energy transfer (FRET) analysis. Dissociation of KIF5B from tubulin after TNF treatment was dependent on JNK activity. Furthermore, TNF inhibited axonal transport of mitochondria and synaptophysin by reducing the mobile fraction via JNK. Thus, TNF produced by activated glial cells in inflammatory or degenerative neurological diseases acts on neurites by acting on the kinesin-tubulin complex and inhibits axonal mitochondria and synaptophysin transport via JNK.
线粒体和突触小泡前体通过驱动蛋白运动蛋白进行的轴突运输对于维持轴突和突触的完整性至关重要。轴突运输紊乱是神经炎症和神经退行性疾病的早期迹象。用炎性细胞因子肿瘤坏死因子-α（TNF）处理培养的神经元会刺激神经突中c-Jun氨基末端激酶（JNK）的磷酸化。通过基于寿命的Förster共振能量转移（FRET）分析确定，TNF处理诱导轴突中驱动蛋白家族5B（KIF5B）重链蛋白与微管蛋白解离，但胞体中未出现这种情况。TNF处理后KIF5B与微管蛋白的解离依赖于JNK活性。此外，TNF通过JNK降低移动部分，从而抑制线粒体和突触素的轴突运输。因此，在炎性或退行性神经疾病中由活化的胶质细胞产生的TNF通过作用于驱动蛋白-微管蛋白复合物作用于神经突，并通过JNK抑制轴突线粒体和突触素运输。
