Ayers Jacob I, Fromholt Susan E, O'Neal Veronica M, Diamond Jeffrey H, Borchelt David R
Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease (CTRND), University of Florida, Box 100159, Gainesville, FL, 32610, USA.
SantaFe HealthCare Alzheimer's Disease Research Center, McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA.
Acta Neuropathol. 2016 Jan;131(1):103-14. doi: 10.1007/s00401-015-1514-0. Epub 2015 Dec 9.
A hallmark feature of amyotrophic lateral sclerosis (ALS) is that symptoms appear to spread along neuroanatomical pathways to engulf the motor nervous system, suggesting a propagative toxic entity could be involved in disease pathogenesis. Evidence for such a propagative entity emerged recently in studies using mice that express G85R-SOD1 mutant protein fused to YFP (G85R-SOD1:YFP). Heterozygous G85R-SOD1:YFP transgenic mice do not develop ALS symptoms out to 20 months of age. However, when newborns are injected with spinal homogenates from paralyzed mutant SOD1 mice, the G85R-SOD1:YFP mice develop paralysis as early as 6 months of age. We now demonstrate that injecting spinal homogenates from paralyzed mutant SOD1 mice into the sciatic nerves of adult G85R-SOD1:YFP mice produces a spreading motor neuron disease within 3.0 ± 0.2 months of injection. The formation of G85R-SOD1:YFP inclusion pathology spreads slowly in this model system; first appearing in the ipsilateral DRG, then lumbar spinal cord, before spreading rostrally up to the cervical cord by the time mice develop paralysis. Reactive astrogliosis mirrors the spread of inclusion pathology and motor neuron loss is most severe in lumbar cord. G85R-SOD1:YFP inclusion pathology quickly spreads to discrete neurons in the brainstem and midbrain that are synaptically connected to spinal neurons, suggesting a trans-synaptic propagation of misfolded protein. Taken together, the data presented here describe the first animal model that recapitulates the spreading phenotype observed in patients with ALS, and implicates the propagation of misfolded protein as a potential mechanism for the spreading of motor neuron disease.
肌萎缩侧索硬化症（ALS）的一个标志性特征是症状似乎沿着神经解剖学通路扩散，进而累及运动神经系统，这表明一种具有传播性的毒性物质可能参与了疾病的发病机制。最近，在使用表达与黄色荧光蛋白（YFP）融合的G85R - SOD1突变蛋白的小鼠进行的研究中，出现了这种具有传播性物质的证据。杂合的G85R - SOD1:YFP转基因小鼠在20个月龄时都不会出现ALS症状。然而，当给新生小鼠注射来自瘫痪的突变SOD1小鼠的脊髓匀浆时，G85R - SOD1:YFP小鼠早在6个月龄时就会出现瘫痪。我们现在证明，将来自瘫痪的突变SOD1小鼠的脊髓匀浆注射到成年G85R - SOD1:YFP小鼠的坐骨神经中，在注射后3.0±0.2个月内会引发一种进行性运动神经元疾病。在这个模型系统中，G85R - SOD1:YFP包涵体病理的形成扩散缓慢；首先出现在同侧背根神经节（DRG），然后是腰脊髓，在小鼠出现瘫痪时，病理向上延伸至颈脊髓。反应性星形胶质细胞增生反映了包涵体病理的扩散，运动神经元损失在腰脊髓最为严重。G85R - SOD1:YFP包涵体病理迅速扩散到脑干和中脑中与脊髓神经元有突触连接的离散神经元，这表明错误折叠蛋白存在跨突触传播。综上所述，本文所呈现的数据描述了首个再现ALS患者中观察到的扩散表型的动物模型，并暗示错误折叠蛋白的传播是运动神经元疾病扩散的一种潜在机制。
