University of California, San Diego, La Jolla, CA, USA.
Acta Neuropathol Commun. 2021 Feb 15;9(1):26. doi: 10.1186/s40478-021-01125-6.
Nucleolar stress has been implicated in the pathology and disease pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) from repeat expansions of GGGGCC in C9orf72 (C9-ALS/FTLD) but not in sporadic ALS (SALS). Previously we reported that antisense RNA transcripts are unique in C9-ALS because of their nucleolar localization in spinal motor neurons and correlation with TDP-43 mislocalization, the hallmark proteinopathy of ALS and FTLD. Here we report our further studies of 11 SALS, 11 C9-ALS and 11 control spinal cords. We find that nucleolar stress manifests specifically as shrinkage in nucleoli of C9-ALS spinal motor neurons. Nucleolar size reduction is greatest in similarly sized alpha motor neurons from C9-ALS cases and results are not skewed by the number of surviving neurons from each ALS spinal cord. Surprisingly, nucleolar shrinkage occurs before main pathological hallmarks-TDP-43 mislocalization or antisense RNA foci-appear and this suggest that nucleolar stress can precede pathology in C9-ALS, findings previously identified in C9-FTLD using sense RNA foci and dipeptide repeat proteins as pathological markers. Importantly, these observations are also seen in SALS motor neurons and thus nucleolar stress appears to be a significant and probably upstream problem in sporadic disease.
核仁应激与肌萎缩侧索硬化症（ALS）和额颞叶变性（FTLD）的病理学和疾病发病机制有关，其病因是 C9orf72 基因中 GGGGCC 重复扩展（C9-ALS/FTLD），但与散发性 ALS（SALS）无关。此前我们报道称，反义 RNA 转录本在 C9-ALS 中是独特的，因为它们在脊髓运动神经元中的核仁定位与 TDP-43 定位错误相关，TDP-43 是 ALS 和 FTLD 的标志性蛋白病。在此，我们报告了对 11 例 SALS、11 例 C9-ALS 和 11 例对照脊髓的进一步研究。我们发现，核仁应激表现为 C9-ALS 脊髓运动神经元核仁的特异性收缩。C9-ALS 病例中大小相似的α运动神经元的核仁缩小最大，而且结果不受每个 ALS 脊髓中存活神经元数量的影响。令人惊讶的是，核仁收缩发生在主要病理标志（TDP-43 定位错误或反义 RNA 病灶）出现之前，这表明核仁应激可能先于 C9-ALS 的病理学发生，这一发现之前使用 sense RNA 病灶和二肽重复蛋白作为病理标志物在 C9-FTLD 中得到了证实。重要的是，这些观察结果也见于 SALS 运动神经元，因此核仁应激似乎是散发性疾病中的一个重要且可能是上游问题。
