Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Box 100159, Gainesville, FL, 32610, USA,
Acta Neuropathol. 2014 Dec;128(6):791-803. doi: 10.1007/s00401-014-1342-7. Epub 2014 Sep 28.
By unknown mechanisms, the symptoms of amyotrophic lateral sclerosis (ALS) seem to spread along neuroanatomical pathways to engulf the motor nervous system. The rate at which symptoms spread is one of the primary drivers of disease progression. One mechanism by which ALS symptoms could spread is by a prion-like propagation of a toxic misfolded protein from cell to cell along neuroanatomic pathways. Proteins that can transmit toxic conformations between cells often can also experimentally transmit disease between individual organisms. To survey the ease with which motor neuron disease (MND) can be transmitted, we injected spinal cord homogenates prepared from paralyzed mice expressing mutant superoxide dismutase 1 (SOD1-G93A and G37R) into the spinal cords of genetically vulnerable SOD1 transgenic mice. From the various models we tested, one emerged as showing high vulnerability. Tissue homogenates from paralyzed G93A mice induced MND in 6 of 10 mice expressing low levels of G85R-SOD1 fused to yellow fluorescent protein (G85R-YFP mice) by 3-11 months, and produced widespread spinal inclusion pathology. Importantly, second passage of homogenates from G93A → G85R-YFP mice back into newborn G85R-YFP mice induced disease in 4 of 4 mice by 3 months of age. Homogenates from paralyzed mice expressing the G37R variant were among those that transmitted poorly regardless of the strain of recipient transgenic animal injected, a finding suggestive of strain-like properties that manifest as differing abilities to transmit MND. Together, our data provide a working model for MND transmission to study the pathogenesis of ALS.
目前尚不清楚的机制导致肌萎缩侧索硬化（ALS）的症状似乎沿着神经解剖通路扩散，从而吞噬运动神经系统。症状扩散的速度是疾病进展的主要驱动因素之一。ALS 症状传播的一种机制可能是通过异常折叠的毒性蛋白类似朊病毒的在沿着神经解剖通路的细胞间传播。能够在细胞间传递毒性构象的蛋白质通常也可以在个体间实验性地传播疾病。为了调查运动神经元疾病（MND）传播的容易程度，我们将表达突变型超氧化物歧化酶 1（SOD1-G93A 和 G37R）的瘫痪小鼠的脊髓匀浆注射到易患 SOD1 转基因小鼠的脊髓中。在我们测试的各种模型中，有一种模型显示出高度易感性。来自瘫痪 G93A 小鼠的组织匀浆在 3-11 个月内诱导 10 只低水平表达与黄色荧光蛋白融合的 G85R-SOD1 的 G85R-YFP 小鼠中的 6 只出现 MND，并产生广泛的脊髓包涵体病理。重要的是，将来自 G93A→G85R-YFP 小鼠的匀浆进行第二次传代，然后将其注射到新生的 G85R-YFP 小鼠中，在 3 个月龄时导致 4 只小鼠发病。无论注射的受体转基因动物的品系如何，表达 G37R 变体的瘫痪小鼠的匀浆都属于传播较差的匀浆之一，这一发现表明存在类似于品系的特性，表现为传播 MND 的不同能力。总之，我们的数据为 MND 传播提供了一个工作模型，以研究 ALS 的发病机制。
