Nuclear lamina invaginations are not a pathological feature of C9orf72 ALS/FTD.
Nuclear lamina invaginations are not a pathological feature of C9orf72 ALS/FTD.
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DOI：
10.1186/s40478-021-01150-5
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发表时间：
2021-03-19
影响因子：
7.1
通讯作者：
Rothstein JD
中科院分区：
文献类型：
--
作者：
Coyne AN;Rothstein JD
家族性和散发性肌萎缩侧索硬化症（ALS）最常见的遗传原因是C9 orf 72基因中的GGGGCC六核苷酸重复扩增（HRE）。虽然C9 orf 72 HRE的直接分子标志（重复RNA灶，二肽重复蛋白病理学）得到了很好的表征，但C9 orf 72 HRE导致ALS和相关神经退行性疾病额颞叶痴呆（FTD）的机制仍然知之甚少。最近，核孔复合物和核质转运的改变已被认为是C9 orf 72 ALS/FTD的重要病理机制。然而，核形态和核纤层本身的全球中断仍然存在争议。在这里，我们使用大量的诱导多能干细胞衍生的脊髓神经元和死后的人运动皮质切片，彻底检查核形态和核层破坏与光学显微镜。与人工过表达模型系统中的先前研究相反，C9 orf 72 HRE的内源性水平不增加核纤层内陷的频率。此外，C9 orf 72 HRE对总体核形状和大小没有影响。值得注意的是，核纤层蛋白B1内陷的频率随着细胞老化而增加，与C9 orf 72 HRE无关。总之，我们的数据表明，核形态在C9 orf 72 ALS/FTD中没有改变。在线版本包含补充材料，可通过10.1186/s40478-021-01150-5获得。
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. The online version contains supplementary material available at 10.1186/s40478-021-01150-5.
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影响因子：
25
作者：
Chou CC;Zhang Y;Umoh ME;Vaughan SW;Lorenzini I;Liu F;Sayegh M;Donlin-Asp PG;Chen YH;Duong DM;Seyfried NT;Powers MA;Kukar T;Hales CM;Gearing M;Cairns NJ;Boylan KB;Dickson DW;Rademakers R;Zhang YJ;Petrucelli L;Sattler R;Zarnescu DC;Glass JD;Rossoll W
通讯作者：
Rossoll W
影响因子：
16.2
作者：
Coyne AN;Zaepfel BL;Hayes L;Fitchman B;Salzberg Y;Luo EC;Bowen K;Trost H;Aigner S;Rigo F;Yeo GW;Harel A;Svendsen CN;Sareen D;Rothstein JD
通讯作者：
Rothstein JD
影响因子：
15.1
作者：
Chew, Jeannie;Cook, Casey;Petrucelli, Leonard
通讯作者：
Petrucelli, Leonard
DOI：
10.1016/s0006-291x(02)00492-8
发表时间：
2002-06-07
影响因子：
3.1
作者：
Pujol, G;Söderqvist, H;Radu, A
通讯作者：
Radu, A
影响因子：
2.9
作者：
Gitler, Aaron D.;Tsuiji, Hitomi
通讯作者：
Tsuiji, Hitomi