Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis.
Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis.
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DOI：
10.1007/s00401-017-1793-8
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发表时间：
2018-03
影响因子：
12.7
通讯作者：
Ravits J
中科院分区：
文献类型：
--
作者：
Saberi S;Stauffer JE;Jiang J;Garcia SD;Taylor AE;Schulte D;Ohkubo T;Schloffman CL;Maldonado M;Baughn M;Rodriguez MJ;Pizzo D;Cleveland D;Ravits J
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。主要假设的致病机制是C9orf72单倍不足和/或来自一种或多种双向转录重复RNA及其二肽重复蛋白（DPR）聚-GP、聚-GA、聚-GR、聚-PR和聚-PA的毒性。最近，核输入和/或输出缺陷，特别是由含精氨酸的多聚-GR或多聚-PR引起的核输入和/或输出缺陷已被提出为基于疾病模型的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DPRs，核孔蛋白和C9orf72蛋白，并将其与ALS的标志蛋白磷酸化TDP-43（pTDP-43）进行比较。在五种DPR中，与不相关区域相比，只有多聚GR在临床相关区域中显著丰富（p <0.001），并且在与pTDP-43共定位的运动皮质中形成树突状聚集体（p <0.0001）。虽然大多数聚GR树突状包涵体是pTDP-43阳性的，但只有4%的pTDP-43树突状包涵体是聚GR阳性的。在神经元的核中染色含精氨酸的多聚GR和多聚PR产生的信号不是C9 ALS特异性的。我们无法检测到C9 ALS中的核标记物RanGap、核纤层蛋白B1和Importin β 1的显著差异，尽管我们观察到与对照相比，C9和非C9 ALS中的细胞核发生了细微变化。C9orf72蛋白本身在大神经元和胶质细胞的细胞质中弥漫表达，并且在临床相关的额叶皮质和不相关的枕叶皮质中减少了近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的运动区中的神经突和pTDP43。这与关于TDP-43在树突中的功能的新出现的想法一致。
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 neurites and pTDP43 in motor regions of C9 ALS CNS. This is consistent with new emerging ideas about TDP-43 functions in dendrites.
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影响因子：
17.1
作者：
Burberry A;Suzuki N;Wang JY;Moccia R;Mordes DA;Stewart MH;Suzuki-Uematsu S;Ghosh S;Singh A;Merkle FT;Koszka K;Li QZ;Zon L;Rossi DJ;Trowbridge JJ;Notarangelo LD;Eggan K
通讯作者：
Eggan K
影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
DOI：
10.1126/science.1254917
发表时间：
2014-09-05
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kwon I;Xiang S;Kato M;Wu L;Theodoropoulos P;Wang T;Kim J;Yun J;Xie Y;McKnight SL
通讯作者：
McKnight SL
影响因子：
2.1
作者：
Ishiguro, Akira;Kimura, Nobuyuki;Ishihama, Akira
通讯作者：
Ishihama, Akira
影响因子：
12.7
作者：
Al-Sarraj, Safa;King, Andrew;Shaw, Christopher E.
通讯作者：
Shaw, Christopher E.