Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK.
J Pathol. 2020 Jan;250(1):67-78. doi: 10.1002/path.5351. Epub 2019 Nov 23.
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 Ca -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.
肌萎缩侧索硬化症（ALS）的特征是运动神经元进行性退化。虽然有超过 40 个基因与因果单基因突变有关，但大多数 ALS 患者并非遗传决定的。因果 ALS 突变正在越来越多地进行机制研究，尽管这些机制在多种已知的家族性 ALS（fALS）和散发性 ALS（sALS）之间以及不同神经元类型之间是如何趋同和发散的，目前还知之甚少。一个与选择性运动神经元死亡有关的共同途径是增强的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）介导的兴奋性毒性。具体来说，人类体外和病理学证据将 C9orf72 重复扩展突变与由于 AMPAR 亚基失调导致的 Ca 通透性 AMPAR 群体的相对增加联系起来。在这里，我们使用 BaseScope 首次对 sALS 和 fALS 中由于 SOD1 和 C9orf72 突变导致的死后下运动神经元（脊髓、前角）、上运动神经元（运动皮层）和前额叶皮层神经元的 AMPAR 亚基转录本的表达谱进行了比较定量评估。我们的数据表明，所有 ALS 病例中的下运动神经元中都存在 AMPAR 失调。然而，sALS 和突变 C9orf72 病例显示 GluA1 上调，而突变 SOD1 病例显示 GluA2 下调。我们还表明，sALS 病例在运动和前额叶皮层中表现出广泛的 AMPAR 失调，尽管调节失调的 AMPAR 亚基的确切身份取决于脑区。相比之下，突变 SOD1 和 C9orf72 病例中的 AMPAR 失调仅局限于下运动神经元。我们的数据突出了 AMPAR 亚基表达的复杂失调，反映了不同脑区和 ALS 队列之间趋同和发散的机制。
