Characterization of early pathogenesis in the SOD1(G93A) mouse model of ALS: part II, results and discussion.
Characterization of early pathogenesis in the SOD1(G93A) mouse model of ALS: part II, results and discussion.
复制标题
DOI：
10.1002/brb3.142
复制
发表时间：
2013-07
影响因子：
3.1
通讯作者：
Milligan C
中科院分区：
文献类型：
--
作者：
Vinsant S;Mansfield C;Jimenez-Moreno R;Del Gaizo Moore V;Yoshikawa M;Hampton TG;Prevette D;Caress J;Oppenheim RW;Milligan C
肌萎缩侧索硬化症 (ALS) 小鼠模型中的病理事件得到了很好的表征，但文献综述未能确定促成疾病病理的特定起始事件。目前，该领域越来越多的共识认为轴突和突触是细胞退化的第一个位点，但对于轴突和突触丧失是在这些位点自主启动还是由细胞体、非神经元细胞甚至非运动神经元 (MN) 中的病理学引发，存在争议。先前的研究已确定突变型超氧化物歧化酶 1 (SOD1) 模型中涉及脊髓、外周轴突、神经肌肉接头 (NMJ) 或肌肉的病理事件；然而，很少有研究在同一研究中系统地检查多个部位的发病机制。我们对 ALS SOD1G93A 小鼠模型的神经肌肉系统的中枢和外周成分进行了超微结构检查。 P60 时 20% 的 MN 会发生退化，但 P30 时快速易疲劳肌肉中的 NMJ 神经支配会减少 40%。 P30 时还发现步态改变和肌肉无力。在最初的 NMJ 去神经之前，轴突运输没有变化。在 P7 时观察到线粒体形态变化，并随着疾病进展而变得更加突出。在 P30 时，兴奋性轴突树突和轴体突触显着减少，而 C 型轴体突触增加。我们的研究检查了周围和中枢神经肌肉系统的早期病理学。肌肉去神经支配与功能性运动缺陷相关，并在 SOD1G93A 小鼠出生后第一个月开始。突触线粒体、MN 体和树突发生生理功能障碍和病理，这些动物的疾病发病比最初认为的早 2 个月以上。这些信息对于设计更有可能影响疾病发作和进展的临床前试验可能很有价值。
Pathological events are well characterized in amyotrophic lateral sclerosis (ALS) mouse models, but review of the literature fails to identify a specific initiating event that precipitates disease pathology. There is now growing consensus in the field that axon and synapses are first cellular sites of degeneration, but controversy exists over whether axon and synapse loss is initiated autonomously at those sites or by pathology in the cell body, in nonneuronal cells or even in nonmotoneurons (MNs). Previous studies have identified pathological events in the mutant superoxide dismutase 1 (SOD1) models involving spinal cord, peripheral axons, neuromuscular junctions (NMJs), or muscle; however, few studies have systematically examined pathogenesis at multiple sites in the same study. We have performed ultrastructural examination of both central and peripheral components of the neuromuscular system in the SOD1G93A mouse model of ALS. Twenty percent of MNs undergo degeneration by P60, but NMJ innervation in fast fatigable muscles is reduced by 40% by P30. Gait alterations and muscle weakness were also found at P30. There was no change in axonal transport prior to initial NMJ denervation. Mitochondrial morphological changes are observed at P7 and become more prominent with disease progression. At P30 there was a significant decrease in excitatory axo-dendritic and axo-somatic synapses with an increase in C-type axo-somatic synapses. Our study examined early pathology in both peripheral and central neuromuscular system. The muscle denervation is associated with functional motor deficits and begins during the first postnatal month in SOD1G93A mice. Physiological dysfunction and pathology in the mitochondria of synapses and MN soma and dendrites occur, and disease onset in these animals begins more than 2 months earlier than originally thought. This information may be valuable for designing preclinical trials that are more likely to impact disease onset and progression.
登录
查看更多内容
影响因子：
5.3
作者：
Fischer, LR;Culver, DG;Glass, JD
通讯作者：
Glass, JD
影响因子：
9.2
作者：
Ferri, A;Sanes, JR;Kato, AC
通讯作者：
Kato, AC
影响因子：
4.4
作者：
Bendotti, C;Calvaresi, N;De Biasi, S
通讯作者：
De Biasi, S
影响因子：
3.5
作者：
CHIU, AY;ZHAI, P;GURNEY, ME
通讯作者：
GURNEY, ME
影响因子：
4.4
作者：
Blijham, Paul J.;Schelhaas, H. Jurgen;Zwarts, Machiel J.
通讯作者：
Zwarts, Machiel J.