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 α-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. © 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

中文翻译：

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散发性ALS死后大脑中AMPA受体亚基表达失调。

肌萎缩性侧索硬化症（ALS）的特征在于进行性运动神经元变性。尽管有40多个与因果单基因突变相关的基因，但大多数ALS患者的遗传因素尚未确定。人们越来越多地对因果ALS突变进行机理研究，尽管人们对这些机制如何在多种已知的ALS家族病因（fALS）和散发性ALS（sALS）之间以及不同神经元类型之间如何趋​​同和分歧进行了研究。涉及选择性运动神经元死亡的一种常见途径是增强的α-氨基-3-羟基-1-甲基-4-异恶唑丙酸酯（AMPAR）介导的兴奋性毒性。具体来说，人类的体外和病理学证据已将C9orf72重复扩增突变与由于AMPAR亚基失调导致的Ca2 +渗透性AMPAR群体相对增加有关。在这里，我们提供了使用BaseScope对死后下运动神经元（脊髓，前角），上运动神经元（运动皮层）和前额叶神经元进行AMPAR亚基转录本表达谱的首次比较定量评估。由于SOD1和C9orf72中的突变，导致sALS和fALS中的皮层。我们的数据表明，在所有ALS病例中，AMPAR失调在下运动神经元中都很明显。但是，sALS和突变的C9orf72病例表现出GluA1上调，而突变的SOD1病例表现出GluA2的下调。我们还发现sALS病例在运动和前额叶皮层中表现出广泛的AMPAR失调，尽管失调的AMPAR亚基的确切身份取决于大脑区域。相比之下，突变SOD1和C9orf72病例中AMPAR失调仅限于下运动神经元。我们的数据强调了AMPAR亚基表达的复杂失调，反映了不同大脑区域之间以及ALS队列之间发挥作用的趋同和趋同机制。©2019作者。John Wiley＆Sons Ltd代表大不列颠及爱尔兰病理学会出版的《病理学杂志》。我们的数据强调了AMPAR亚基表达的复杂失调，反映了不同大脑区域之间以及ALS队列之间发挥作用的趋同和趋同机制。©2019作者。John Wiley＆Sons Ltd代表大不列颠及爱尔兰病理学会出版的《病理学杂志》。我们的数据强调了AMPAR亚基表达的复杂失调，反映了不同大脑区域之间以及ALS队列之间发挥作用的趋同和趋同机制。©2019作者。John Wiley＆Sons Ltd代表大不列颠及爱尔兰病理学会出版的《病理学杂志》。