Hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (C9 ALS). The main hypothesized pathogenic mechanisms are C9orf72 haploinsufficiency and/or toxicity from one or more of bi-directionally transcribed repeat RNAs and their dipeptide repeat proteins (DPRs) poly-GP, poly-GA, poly-GR, poly-PR and poly-PA. Recently, nuclear import and/or export defects especially caused by arginine-containing poly-GR or poly-PR have been proposed as significant contributors to pathogenesis based on disease models. We quantitatively studied and compared DPRs, nuclear pore proteins and C9orf72 protein in clinically related and clinically unrelated regions of the central nervous system, and compared them to phosphorylated TDP-43 (pTDP-43), the hallmark protein of ALS. Of the five DPRs, only poly-GR was significantly abundant in clinically related areas compared to unrelated areas (p < 0.001), and formed dendritic-like aggregates in the motor cortex that co-localized with pTDP-43 (p < 0.0001). While most poly-GR dendritic inclusions were pTDP-43 positive, only 4% of pTDP-43 dendritic inclusions were poly-GR positive. Staining for arginine-containing poly-GR and poly-PR in nuclei of neurons produced signals that were not specific to C9 ALS. We could not detect significant differences of nuclear markers RanGap, Lamin B1, and Importin β1 in C9 ALS, although we observed subtle nuclear changes in ALS, both C9 and non-C9, compared to control. The C9orf72 protein itself was diffusely expressed in cytoplasm of large neurons and glia, and nearly 50% reduced, in both clinically related frontal cortex and unrelated occipital cortex, but not in cerebellum. In summary, sense-encoded poly-GR DPR was unique, and localized to dendrites and pTDP43 in motor regions of C9 ALS CNS. This is consistent with new emerging ideas about TDP-43 functions in dendrites.

中文翻译：

---

有义编码的聚 GR 二肽重复蛋白与神经变性相关，并且与 TDP-43 独特地共定位于重复扩展的 C9orf72 肌萎缩侧索硬化症的树突中。


C9orf72 中的六核苷酸重复扩增是肌萎缩侧索硬化症 (C9 ALS) 最常见的遗传原因。假设的主要致病机制是 C9orf72 单倍体不足和/或来自一种或多种双向转录重复 RNA 及其二肽重复蛋白 (DPR)、poly-GP、poly-GA、poly-GR、poly-PR 和 poly-PA 的毒性。最近，基于疾病模型，特别是由含精氨酸的聚-GR或聚-PR引起的核输入和/或输出缺陷被认为是发病机制的重要贡献者。我们定量研究和比较了中枢神经系统临床相关和临床无关区域的 DPR、核孔蛋白和 C9orf72 蛋白，并将它们与 ALS 标志蛋白磷酸化 TDP-43 (pTDP-43) 进行比较。在五个 DPR 中，与不相关区域相比，只有 Poly-GR 在临床相关区域显着丰富 (p < 0.001)，并在运动皮层中形成与 pTDP-43 共定位的树突状聚集体 (p < 0.0001) ）。虽然大多数聚-GR 树突状内含物为 pTDP-43 阳性，但只有 4% 的 pTDP-43 树突状内含物为聚-GR 阳性。对神经元细胞核中含有精氨酸的聚 GR 和聚 PR 进行染色，产生的信号并非 C9 ALS 特有的信号。尽管我们观察到与对照相比，ALS（C9 和非 C9）中细微的核变化，但我们无法检测到 C9 ALS 中核标记 RanGap、Lamin B1 和 Importin β1 的显着差异。 C9orf72蛋白本身在大神经元和神经胶质细胞的细胞质中广泛表达，并且在临床相关的额叶皮层和不相关的枕叶皮层中减少了近50%，但在小脑中没有。 总之，有义编码的多聚 GR DPR 是独特的，并且定位于 C9 ALS CNS 运动区的树突和 pTDP43。这与 TDP-43 在树突中的功能的新观点是一致的。