Prion-like propagation of mutant SOD1 misfolding and motor neuron disease spread along neuroanatomical pathways.
Prion-like propagation of mutant SOD1 misfolding and motor neuron disease spread along neuroanatomical pathways.
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DOI：
10.1007/s00401-015-1514-0
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发表时间：
2016-01
影响因子：
12.7
通讯作者：
Borchelt DR
中科院分区：
文献类型：
--
作者：
Ayers JI;Fromholt SE;O'Neal VM;Diamond JH;Borchelt DR
肌萎缩侧索硬化症（ALS）的一个标志性特征是症状似乎沿着沿着神经解剖学通路扩散以吞噬运动神经系统，这表明一种传播性毒性实体可能参与疾病的发病机制。最近在使用表达与YFP融合的G85 R-SOD 1突变蛋白（G85 R-SOD 1：YFP）的小鼠的研究中出现了这种繁殖实体的证据。杂合子G85 R-SOD 1：YFP转基因小鼠在20个月大之前不会出现ALS症状。然而，当新生儿被注射来自瘫痪的突变SOD 1小鼠的脊髓匀浆时，G85 R-SOD 1：YFP小鼠早在6个月大时就出现瘫痪。我们现在证明，将瘫痪的突变SOD 1小鼠的脊髓匀浆注射到成年G85 R-SOD 1：YFP小鼠的坐骨神经中，在注射后3.0 ± 0.2个月内产生扩散性运动神经元疾病。G85 R-S 0 D1：YFP包涵体病理的形成在该模型系统中缓慢扩散;首先出现在同侧DRG中，然后出现在腰脊髓中，然后在小鼠发生瘫痪时嘴部扩散到颈脊髓。反应性星形胶质细胞增生反映了包涵体病理学的扩散，运动神经元丢失在腰髓中最为严重。G85 R-SOD 1：YFP包涵体病理学迅速扩散到脑干和中脑中与脊髓神经元突触连接的离散神经元，表明错误折叠蛋白质的跨突触传播。总之，这里提供的数据描述了第一个动物模型，概括了在ALS患者中观察到的扩散表型，并暗示错误折叠蛋白的传播是运动神经元疾病扩散的潜在机制。
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.