Dysregulation of AMPA receptor subunit expression in sporadic ALS post-mortem brain
Dysregulation of AMPA receptor subunit expression in sporadic ALS post-mortem brain
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DOI：
10.1002/path.5351
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发表时间：
2019-11-23
影响因子：
7.3
通讯作者：
Smith, Colin
中科院分区：
文献类型：
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作者：
Gregory, Jenna M.;Livesey, Matthew R.;Smith, Colin
肌萎缩侧索硬化症(ALS)的特征是进行性运动神经元变性。虽然有40多个基因与因果单基因突变有关，但大多数ALS患者并不是由基因决定的。ALS基因突变的机制研究越来越多，但这些机制如何在ALS的多个已知家族性原因(FALS)和散发性ALS(SALS)之间以及不同神经元类型之间汇聚和分化的机制尚不清楚。选择性运动神经元死亡的一种常见途径是增强alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate(AMPAR)介导的兴奋性。具体地说，人类体外和病理证据已经将C9orf72重复扩展突变与由于AMPAR亚单位失调而导致的钙离子渗透性AMPAR种群的相对增加联系在一起。在这里，我们首次使用BaseScope对由于SOD1和C9orf72突变而导致的SALS和FAL的下运动神经元(脊髓、前角)、上运动神经元(运动皮质)和前额叶皮质神经元中AMPAR亚单位转录本的表达谱进行了比较定量评估。我们的数据表明，在所有ALS病例中，AMPAR异常在下运动神经元中都是显著的。SALS和突变型C9orf72例GluA1表达上调，而突变型SOD1GluA2表达下调。我们还发现SALS病例在运动和前额叶皮质表现出广泛的AMPAR失调，尽管AMPAR亚单位失调的确切身份取决于大脑区域。相反，突变型SOD1和C9orf72例AMPAR异常仅限于低位运动神经元。我们的数据突出了AMPAR亚单位表达的复杂失调，反映了不同脑区和ALS队列之间发挥作用的汇聚和发散机制。(三)2019名作者。《病理学杂志》由John Wiley&Sons Ltd代表大不列颠和爱尔兰病理学会出版。
Amyotrophic lateral sclerosis (ALS) is characterised by progressive motor neuron degeneration. Although there are over 40 genes associated with causal monogenetic mutations, the majority of ALS patients are not genetically determined. Causal ALS mutations are being increasingly mechanistically studied, though how these mechanisms converge and diverge between the multiple known familial causes of ALS (fALS) and sporadic forms of ALS (sALS) and furthermore between different neuron types, is poorly understood. One common pathway that is implicated in selective motor neuron death is enhanced alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPAR)-mediated excitoxicity. Specifically, human in vitro and pathological evidence has linked the C9orf72 repeat expansion mutation to a relative increase in the Ca2+-permeable AMPAR population due to AMPAR subunit dysregulation. Here, we provide the first comparative quantitative assessment of the expression profile of AMPAR subunit transcripts, using BaseScope, in post-mortem lower motor neurons (spinal cord, anterior horn), upper motor neurons (motor cortex) and neurons of the pre-frontal cortex in sALS and fALS due to mutations in SOD1 and C9orf72. Our data indicated that AMPAR dysregulation is prominent in lower motor neurons in all ALS cases. However, sALS and mutant C9orf72 cases exhibited GluA1 upregulation whereas mutant SOD1 cases displayed GluA2 down regulation. We also showed that sALS cases exhibited widespread AMPAR dysregulation in the motor and pre-frontal cortex, though the exact identity of the AMPAR subunit being dysregulated was dependent on brain region. In contrast, AMPAR dysregulation in mutant SOD1 and C9orf72 cases was restricted to lower motor neurons only. Our data highlight the complex dysregulation of AMPAR subunit expression that reflects both converging and diverging mechanisms at play between different brain regions and between ALS cohorts. (c) 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.