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Nat & Nat Neurosci:核转运问题或和肌萎缩侧索硬化症发病直接相关

  1. C9orf72
  2. 发病
  3. 核转运
  4. 肌萎缩侧索硬化症
  5. 额颞退化

来源:生物谷 2015-10-24 11:07

近日,刊登在国际著名杂志Nature及其子刊Nature Neuroscience上的三篇研究论文中,来自美国国立卫生研究院的三组科学家通过研究阐明了和某些形式的肌萎缩侧索硬化(ALS)和额颞退化(FTD)发病相关的基因突变,这两种疾病常常通过干扰细胞核内外物质的运动来破坏神经元的功能。

图片来源:medicalxpress.com

2015年10月23日 讯 /生物谷BIOON/ --近日,刊登在国际著名杂志Nature及其子刊Nature Neuroscience上的三篇研究论文中,来自美国国立卫生研究院的三组科学家通过研究阐明了和某些形式的肌萎缩侧索硬化(ALS)和额颞退化(FTD)发病相关的基因突变,这两种疾病常常通过干扰细胞核内外物质的运动来破坏神经元的功能。

研究者Amelie Gubitz博士指出,本文研究为揭示核转运对神经元健康的重要性提供了新的线索,ALS和FTD两种疾病均是由特殊神经元的死亡而引发,在ALS疾病中,患者常会出现运动困难,最终会发生瘫痪等,而在FTD中,患者往往会经历语言和决策制定等问题。此前研究中,研究者将C9orf72基因的特殊突变同40%的ALS病例和25%的遗传性FTD病例直接联系起来。

而在本文研究中,研究者发现,C9orf72基因的突变会损伤患者皮肤细胞神经元中的核转运过程;相比健康对照细胞而言,患者皮肤细胞的神经元包含有较多的RNA,这就表明,基因的突变会抑制RNA离开细胞核,另外两组研究者则发现,病人机体衍生的神经元不能将特定的蛋白质带入细胞核。这项研究中,研究者重点研究了C9orf72基因突变引发的异常RNA如何影响一种名为RanGAP蛋白的功能,RanGAP对于细胞将物质运输进细胞核非常必要。

基于此前的研究结果,研究小组证实,RNA链可以结合携带突变的患者大脑组织中的RanGAP蛋白,并且阻断该蛋白功能的展现,随后研究者利用化合物抑制神经元细胞的功能,结果发现这可以消除物质运输的缺陷,使得蛋白质可以进入细胞核中能够,类似地,增加果蝇机体中RanGAP蛋白的产生可以减少因突变引发的神经元的退化及运动问题的发生。

研究者Taylor表示,我们非常吃惊可以发现18个基因和核细胞质穿梭转运直接相关,后期我们还将开展更多深入的研究来开发新型疗法,增加核与质之间的运输从而帮助治疗FTD和ALS。(生物谷Bioon.com)

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The C9orf72 repeat expansion disrupts nucleocytoplasmic transport

Ke Zhang, Christopher J. Donnelly, Aaron R. Haeusler, Jonathan C. Grima, James B. Machamer, Peter Steinwald, Elizabeth L. Daley, Sean J. Miller, Kathleen M. Cunningham, Svetlana Vidensky, Saksham Gupta, Michael A. Thomas, Ingie Hong, Shu-Ling Chiu, Richard L. Huganir, Lyle W. Ostrow, Michael J. Matunis, Jiou Wang, Rita Sattler, Thomas E. Lloyd & Jeffrey D. Rothstein

The hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G4C2 RNA including RanGAP1. A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.

GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport

Brian D. Freibaum, Yubing Lu, Rodrigo Lopez-Gonzalez, Nam Chul Kim, Sandra Almeida, Kyung-Ha Lee, Nisha Badders, Marc Valentine, Bruce L. Miller, Philip C. Wong, Leonard Petrucelli, Hong Joo Kim, Fen-Biao Gao & J. Paul Taylor

The GGGGCC (G4C2) repeat expansion in a noncoding region of C9orf72 is the most common cause of sporadic and familial forms of amyotrophic lateral sclerosis and frontotemporal dementia1, 2. The basis for pathogenesis is unknown. To elucidate the consequences of G4C2 repeat expansion in a tractable genetic system, we generated transgenic fly lines expressing 8, 28 or 58 G4C2-repeat-containing transcripts that do not have a translation start site (AUG) but contain an open-reading frame for green fluorescent protein to detect repeat-associated non-AUG (RAN) translation. We show that these transgenic animals display dosage-dependent, repeat-length-dependent degeneration in neuronal tissues and RAN translation of dipeptide repeat (DPR) proteins, as observed in patients with C9orf72-related disease. This model was used in a large-scale, unbiased genetic screen, ultimately leading to the identification of 18 genetic modifiers that encode components of the nuclear pore complex (NPC), as well as the machinery that coordinates the export of nuclear RNA and the import of nuclear proteins. Consistent with these results, we found morphological abnormalities in the architecture of the nuclear envelope in cells expressing expanded G4C2 repeats in vitro and in vivo. Moreover, we identified a substantial defect in RNA export resulting in retention of RNA in the nuclei of Drosophila cells expressing expanded G4C2 repeats and also in mammalian cells, including aged induced pluripotent stem-cell-derived neurons from patients with C9orf72-related disease. These studies show that a primary consequence of G4C2 repeat expansion is the compromise of nucleocytoplasmic transport through the nuclear pore, revealing a novel mechanism of neurodegeneration.

Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS

Ana Jovičić, Jerome Mertens, Steven Boeynaems, Elke Bogaert, Noori Chai, Shizuka B Yamada, Joseph W Paul III, Shuying Sun, Joseph R Herdy, Gregor Bieri, Nicholas J Kramer, Fred H Gage, Ludo Van Den Bosch, Wim Robberecht & Aaron D Gitler

9orf72 mutations are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dipeptide repeat proteins (DPRs) produced by unconventional translation of the C9orf72 repeat expansions cause neurodegeneration in cell culture and in animal models. We performed two unbiased screens in Saccharomyces cerevisiae and identified potent modifiers of DPR toxicity, including karyopherins and effectors of Ran-mediated nucleocytoplasmic transport, providing insight into potential disease mechanisms and therapeutic targets.

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