Cell-to-Cell Transmission of Dipeptide Repeat Proteins Linked to C9orf72-ALS/FTD.
Cell-to-Cell Transmission of Dipeptide Repeat Proteins Linked to C9orf72-ALS/FTD.
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与C9ORF72-ALS/FTD相关的二肽重复蛋白的细胞向细胞传播。
DOI：
10.1016/j.celrep.2016.09.032
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发表时间：
2016-10-11
期刊：
影响因子：
8.8
通讯作者：
Trotti D
中科院分区：
文献类型：
--
作者：
Westergard T;Jensen BK;Wen X;Cai J;Kropf E;Iacovitti L;Pasinelli P;Trotti D
C9 orf 72中异常的六核苷酸重复扩增是肌萎缩侧索硬化（ALS）和额颞叶痴呆（FTD）最常见的遗传变化。含有这些扩增片段的RNA转录物进行重复相关的非ATG（RAN）翻译，形成五个二肽重复蛋白（DPR）。在C9 orf 72-ALS/FTD患者的CNS中发现DPR作为聚集体存在，并且当在体外神经元培养物和体内动物模型中表达时，一些DPR会引起变性。特征性疾病相关蛋白的传播驱动许多神经退行性疾病的病理进展。虽然DPR的毒性机制仍在研究中，但DPR传播的可能性尚未确定。利用不同的实验细胞培养平台，包括来自C9 orf 72-ALS患者的诱导多能干细胞的脊髓运动神经元，我们发现了DPR通过外泌体依赖性和独立途径的细胞间传播的证据，这可能与疾病有关。eTOC：Westergard等人在体外和动物模型中研究了与C9 orf 72-ALS/FTD相关的二肽重复蛋白的细胞间扩散。他们认为，跨细胞传递可以解释在人类死后CNS区域中观察到的聚集表达模式以及这些疾病的进行性神经变性。
Aberrant hexanucleotide repeat expansions in C9orf72 are the most common genetic change underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). RNA transcripts containing these expansions undergo repeat associated non-ATG (RAN) translation to form five dipeptide repeat proteins (DPRs). DPRs are found as aggregates throughout the CNS of C9orf72-ALS/FTD patients and some cause degeneration when expressed in vitro in neuronal cultures and in vivo in animal models. The spread of characteristic disease-related proteins drives the progression of pathology in many neurodegenerative diseases. While DPR toxic mechanisms continue to be investigated, the potential for DPRs to spread has yet to be determined. Utilizing different experimental cell culture platforms, including spinal motor neurons derived from induced pluripotent stem cells from C9orf72-ALS patients, we found evidence for cell-to-cell spreading of DPRs via exosome-dependent and independent pathways, which may potentially be relevant to disease. eTOC: Westergard et al. examine the cell-to-cell spread of dipeptide repeat proteins related to C9orf72-ALS/FTD in vitro and in animal models. They suggest that transcellular transmission may explain the clustered expression pattern seen in human post-mortem CNS areas as well as the progressive neurodegeneration of these diseases.
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影响因子：
5.8
作者：
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通讯作者：
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影响因子：
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