Simic Goran
Department of Neuroscience, Croatian Institute for Brain Research, School of Medicine, Zagreb University, Salata 12, 10000, Zagreb, Croatia.
Acta Neuropathol. 2008 Sep;116(3):223-34. doi: 10.1007/s00401-008-0411-1. Epub 2008 Jul 16.
Although it is known that deletions or mutations of the SMN1 gene on chromosome 5 cause decreased levels of the SMN protein in subjects with proximal autosomal recessive spinal muscular atrophy (SMA), the exact sequence of pathological events leading to selective motoneuron cell death is not fully understood yet. In this review, new findings regarding the dual cellular role of the SMN protein (translocation of beta-actin to axonal growth cones and snRNP biogenesis/pre-mRNA splicing) were integrated with recent data obtained by detailed neuropathological examination of SMA and control subjects. A presumptive series of 10 pathogenetic events for SMA is proposed as follows: (1) deletions or mutations of the SMN1 gene, (2) increased SMN mRNA decay and reduction in full-length functional SMN protein, (3) impaired motoneuron axono- and dendrogenesis, (4) failure of motoneurons to form synapses with corticospinal fibers from upper motoneurons, (5) abnormal motoneuron migration towards ventral spinal roots, (6) inappropriate persistence of motoneuron apoptosis due to impaired differentiation and motoneuron displacement, (7) substantial numbers of motoneurons continuing to migrate abnormally ("heterotopic motoneurons") and entering into the ventral roots, (8) attracted glial cells following these heterotopic motoneurons, which form the glial bundles of ventral roots, (9) impaired axonal transport of actin, causing remaining motoneurons to become chromatolytic, and (10) eventual death of all apoptotic, heterotopic and chromatolytic neurons, with apoptosis being more rapid and predominating in the earlier stages, with death of heterotopic and chromatolytic neurons occurring more slowly by necrosis during the later stages of SMA. According to this model, the motoneuron axonopathy is more important for pathogenesis than the ubiquitous nuclear splicing deficit. It is also supposed that individually variable levels of SMN protein, together with influences of other phenotype modifier genes and their products, cause the clinical SMA spectrum through differential degree of motoneuron functional loss.
虽然已知5号染色体上SMN1基因的缺失或突变会导致近端常染色体隐性脊髓性肌萎缩症（SMA）患者体内SMN蛋白水平降低，但导致选择性运动神经元细胞死亡的病理事件的确切顺序尚未完全明确。在本综述中，关于SMN蛋白双重细胞作用（β-肌动蛋白向轴突生长锥的转运以及小核核糖核蛋白生物合成/前体mRNA剪接）的新发现与近期通过对SMA患者和对照受试者进行详细神经病理学检查所获得的数据相结合。提出了一个关于SMA的推定的10个致病事件系列，如下：（1）SMN1基因的缺失或突变，（2）SMN mRNA降解增加和全长功能性SMN蛋白减少，（3）运动神经元轴突和树突发生受损，（4）运动神经元无法与上位运动神经元的皮质脊髓纤维形成突触，（5）运动神经元向腹侧脊髓神经根异常迁移，（6）由于分化受损和运动神经元移位导致运动神经元凋亡不适当持续存在，（7）大量运动神经元继续异常迁移（“异位运动神经元”）并进入腹侧神经根，（8）这些异位运动神经元吸引神经胶质细胞，形成腹侧神经根的神经胶质束，（9）肌动蛋白的轴突运输受损，导致剩余运动神经元发生染色质溶解，以及（10）所有凋亡、异位和染色质溶解神经元最终死亡，凋亡在早期阶段更快且占主导，而异位和染色质溶解神经元的死亡在SMA后期通过坏死发生得更慢。根据该模型，运动神经元轴突病在发病机制中比普遍存在的核剪接缺陷更重要。还推测，SMN蛋白的个体可变水平，连同其他表型修饰基因及其产物的影响，通过运动神经元功能丧失的不同程度导致临床SMA谱。
