Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Acta Neuropathol Commun. 2021 Mar 19;9(1):45. doi: 10.1186/s40478-021-01150-5.
The most common genetic cause of familial and sporadic amyotrophic lateral sclerosis (ALS) is a GGGGCC hexanucleotide repeat expansion (HRE) in the C9orf72 gene. While direct molecular hallmarks of the C9orf72 HRE (repeat RNA foci, dipeptide repeat protein pathology) are well characterized, the mechanisms by which the C9orf72 HRE causes ALS and the related neurodegenerative disease frontotemporal dementia (FTD) remain poorly understood. Recently, alterations to the nuclear pore complex and nucleocytoplasmic transport have been accepted as a prominent pathomechanism underlying C9orf72 ALS/FTD. However, global disruptions to nuclear morphology and the nuclear lamina itself remain controversial. Here, we use a large number of induced pluripotent stem cell derived spinal neurons and postmortem human motor cortex sections to thoroughly examine nuclear morphology and nuclear lamina disruptions with light microscopy. In contrast to previous studies in artificial overexpression model systems, endogenous levels of the C9orf72 HRE do not increase the frequency of nuclear lamina invaginations. In addition, the C9orf72 HRE has no impact on overall nuclear shape and size. Notably, the frequency of nuclear Lamin B1 invaginations increases with cellular aging, independent of the C9orf72 HRE. Together, our data suggest that nuclear morphology is unaltered in C9orf72 ALS/FTD.
最常见的家族性和散发性肌萎缩侧索硬化症（ALS）的遗传原因是 C9orf72 基因中的 GGGGCC 六核苷酸重复扩增（HRE）。虽然 C9orf72 HRE 的直接分子特征（重复 RNA 焦点、二肽重复蛋白病理学）已得到很好的描述，但 C9orf72 HRE 导致 ALS 和相关神经退行性疾病额颞叶痴呆（FTD）的机制仍知之甚少。最近，核孔复合体和核质转运的改变被认为是 C9orf72 ALS/FTD 的主要病理机制。然而，核形态和核纤层本身的全局破坏仍然存在争议。在这里，我们使用大量诱导多能干细胞衍生的脊髓神经元和死后人类运动皮层切片，通过光学显微镜彻底检查核形态和核纤层的破坏。与之前在人工过表达模型系统中的研究相反，内源性 C9orf72 HRE 水平不会增加核纤层内陷的频率。此外，C9orf72 HRE 对整体核形状和大小没有影响。值得注意的是，核层蛋白 B1 内陷的频率随着细胞衰老而增加，与 C9orf72 HRE 无关。总之，我们的数据表明 C9orf72 ALS/FTD 中的核形态未改变。
