Loss of translation elongation factor (eEF1A2) expression in vivo differentiates between Wallerian degeneration and dying-back neuronal pathology
Loss of translation elongation factor (eEF1A2) expression in vivo differentiates between Wallerian degeneration and dying-back neuronal pathology
复制标题
DOI：
10.1111/j.1469-7580.2008.01007.x
复制
发表时间：
2008-12-01
影响因子：
2.4
通讯作者：
Gillingwater, Thomas H.
中科院分区：
文献类型：
--
作者：
Murray, Lyndsay M.;Thomson, Derek;Gillingwater, Thomas H.
Wallerian变性和回死病理学是两种众所周知的能够调节体内神经元轴突和突触隔室的破坏和损失的细胞途径。然而，这些途径的潜在机制和分子触发因素仍然难以捉摸。在这里，我们表明，翻译延伸因子eEF1A2表达的纯合子Wasted小鼠的下运动神经元和骨骼肌纤维的损失引发了回退性神经病变。神经肌肉接头处的突触丢失发生在轴突病理学之前，其机制在形态学上与沃勒变性不同。在衰老小鼠中的回死病理学伴随着锌指蛋白ZPR 1表达水平的降低，如在其他回死神经病如脊髓性肌萎缩症中所发现的。令人惊讶的是，实验性神经损伤显示，华勒变性显着延迟纯合子Wasted小鼠;形态学评估显示，80%的神经肌肉接头在深蚓状肌在24小时和50%在48小时保留运动神经末梢胫神经损伤后。这与野生型和杂合Wasted小鼠形成对比，其中在损伤后24小时，<5%的神经肌肉接头保留运动神经末梢。这些数据表明，需要eEF1A2表达来防止体内神经肌肉接头处的回死病理的开始。相反，eEF1A2表达的缺失显著抑制体内沃勒变性的开始和进展。我们得出的结论是，eEF 1A 2表达的丧失将体内退行性病变的潜在机制与沃勒变性的机制区分开来，并表明eEF 1A 2依赖性级联可能提供新的分子靶点来操纵下运动神经元的神经退行性途径。
Wallerian degeneration and dying-back pathology are two well-known cellular pathways capable of regulating the breakdown and loss of axonal and synaptic compartments of neurons in vivo. However, the underlying mechanisms and molecular triggers of these pathways remain elusive. Here, we show that loss of translation elongation factor eEF1A2 expression in lower motor neurons and skeletal muscle fibres in homozygous Wasted mice triggered a dying-back neuropathy. Synaptic loss at the neuromuscular junction occurred in advance of axonal pathology and by a mechanism morphologically distinct from Wallerian degeneration. Dying-back pathology in Wasted mice was accompanied by reduced expression levels of the zinc finger protein ZPR1, as found in other dying-back neuropathies such as spinal muscular atrophy. Surprisingly, experimental nerve lesion revealed that Wallerian degeneration was significantly delayed in homozygous Wasted mice; morphological assessment revealed that 80% of neuromuscular junctions in deep lumbrical muscles at 24 h and 50% at 48 h had retained motor nerve terminals following tibial nerve lesion. This was in contrast to wild-type and heterozygous Wasted mice where < 5% of neuromuscular junctions had retained motor nerve terminals at 24 h post-lesion. These data show that eEF1A2 expression is required to prevent the initiation of dying-back pathology at the neuromuscular junction in vivo. In contrast, loss of eEF1A2 expression significantly inhibited the initiation and progression of Wallerian degeneration in vivo. We conclude that loss of eEF1A2 expression distinguishes mechanisms underlying dying-back pathology from those responsible for Wallerian degeneration in vivo and suggest that eEF1A2-dependent cascades may provide novel molecular targets to manipulate neurodegenerative pathways in lower motor neurons.