Axonal defects in mouse models of motoneuron disease
Axonal defects in mouse models of motoneuron disease
复制标题
DOI：
10.1002/neu.10313
复制
发表时间：
2004-02-05
期刊：
影响因子：
--
通讯作者：
Sendtner, M
中科院分区：
文献类型：
--
作者：
Jablonka, S;Wiese, S;Sendtner, M
人类运动神经元疾病的特征在于运动终板的丧失、轴突变性和运动神经元的细胞死亡。对家族性ALS、脊髓性肌萎缩症（SMA）和脊髓性肌萎缩伴呼吸窘迫（SMARD）的潜在基因缺陷的鉴定已经指出了导致该疾病的各种形式的不同病理生理机制。来自小鼠模型的累积证据表明，对促凋亡刺激的增强的脆弱性和敏感性仅对一些但不是所有形式的运动神经元疾病负责。在几种自发和ENU（乙基亚硝基脲）诱变的小鼠模型中，以及在动力蛋白p150亚基突变的患者中，调节微管组装和轴突运输机制是有缺陷的。最近的证据表明，轴突生长缺陷有助于显着脊髓性肌萎缩症的病理生理。负责SMA的运动神经元存活蛋白水平降低导致运动神经元中RNA加工受到干扰。这也可能影响β-肌动蛋白和其他蛋白质的mRNA的轴突运输，这些蛋白质在轴突生长和突触功能中发挥重要作用。特定蛋白的局部翻译可能受到影响，因为发育中的运动神经元在远端轴突和生长锥中含有核糖体样结构。总之，来自这些小鼠模型的证据和来自患者的新遗传数据表明，轴突生长和维持涉及多种机制，包括微管组装和蛋白质和核糖核蛋白（RNP）的轴突运输。因此，轴突维护的缺陷可能在几种形式的人类运动神经元疾病的发展中起主导作用。(C)2003 Wiley Periodicals，Inc.
Human motoneuron disease is characterized by loss of motor endplates, axonal degeneration, and cell death of motoneurons. The identification of the underlying gene defects for familial ALS, spinal muscular atrophy (SMA), and spinal muscular atrophy with respiratory distress (SMARD) has pointed to distinct pathophysiological mechanisms that are responsible for the various forms of the disease. Accumulating evidence from mouse models suggests that enhanced vulnerability and sensitivity to proapoptotic stimuli is only responsible for some but not all forms of motoneuron disease. Mechanisms that modulate microtubule assembly and the axonal transport machinery are defective in several spontaneous and ENU (ethylnitrososurea) mutagenized mouse models but also in patients with mutations in the p150 subunit of dynactin. Recent evidence suggests that axonal growth defects contribute significantly to the pathophysiology of spinal muscular atrophy. Reduced levels of the survival motoneuron protein that are responsible for SMA lead to disturbed RNA processing in motoneurons. This could also affect axonal transport of mRNAs for beta-actin and other proteins that play an essential role in axon growth and synaptic function. The local translation of specific proteins might be affected, because developing motoneurons contain ribosome-like structures in distal axons and growth cones. Altogether, the evidence from these mouse models and the new genetic data from patients suggest that axon growth and maintenance involves a variety of mechanisms, including microtubule assembly and axonal transport of proteins and ribonucleoproteins (RNPs). Thus, defects in axon maintenance could play a leading role in the development of several forms of human motoneuron disease. (C) 2003 Wiley Periodicals, Inc.