The pro-apoptotic JNK scaffold POSH/SH3RF1 mediates CHMP2BIntron5-associated toxicity in animal models of frontotemporal dementia.
The pro-apoptotic JNK scaffold POSH/SH3RF1 mediates CHMP2BIntron5-associated toxicity in animal models of frontotemporal dementia.
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DOI：
10.1093/hmg/ddy048
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发表时间：
2018-04-15
影响因子：
3.5
通讯作者：
Sweeney ST
中科院分区：
文献类型：
--
作者：
West RJH;Ugbode C;Gao FB;Sweeney ST
额颞叶痴呆（FTD）是早发性痴呆最常见的形式之一。然而，FTD中驱动神经元萎缩的病理机制仍知之甚少。在这里，我们确定了一个保守的作用，新的促凋亡蛋白大量的SH 3（POSH）/SH 3结构域含有环指1介导的神经病理学在果蝇和哺乳动物模型的带电多泡体蛋白2B（CHMP 2BIntron 5）相关的FTD。在表达CHMP 2BIntron 5的果蝇和小鼠的整个神经系统中观察到POSH的异常、AKT依赖性积累。POSH的敲除被证明是神经保护性的，并且足以减轻果蝇模型中的异常神经元形态、行为缺陷和过早致死，以及表达CHMP 2BIntron 5的大鼠原代神经元中的树突崩溃和细胞死亡。在果蝇和哺乳动物模型中，POSH敲低也改善了Jun N-末端激酶和凋亡级联的标记物升高。本研究首次将POSH表征为FTD神经病理学的潜在组分，确定了与FTD谱相关的新凋亡途径。
Frontotemporal dementia (FTD) is one of the most prevalent forms of early-onset dementia. However, the pathological mechanisms driving neuronal atrophy in FTD remain poorly understood. Here we identify a conserved role for the novel pro-apoptotic protein plenty of SH3s (POSH)/SH3 domain containing ring finger 1 in mediating neuropathology in Drosophila and mammalian models of charged multivesicular body protein 2B (CHMP2BIntron5) associated FTD. Aberrant, AKT dependent, accumulation of POSH was observed throughout the nervous system of both Drosophila and mice expressing CHMP2BIntron5. Knockdown of POSH was shown to be neuroprotective and sufficient to alleviate aberrant neuronal morphology, behavioral deficits and premature-lethality in Drosophila models, as well as dendritic collapse and cell death in CHMP2BIntron5expressing rat primary neurons. POSH knockdown also ameliorated elevated markers of Jun N-terminal kinase and apoptotic cascades in both Drosophila and mammalian models. This study provides the first characterization of POSH as a potential component of an FTD neuropathology, identifying a novel apoptotic pathway with relevance to the FTD spectrum.
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影响因子：
6.9
作者：
Gao X;Zhang H;Steinberg G;Zhao H
通讯作者：
Zhao H
DOI：
10.1073/pnas.0903134106
发表时间：
2009-07-21
影响因子：
11.1
作者：
Ahmad, S. Tariq;Sweeney, Sean T.;Gao, Fen-Biao
通讯作者：
Gao, Fen-Biao
影响因子：
--
作者：
Corbier, Camille;Sellier, Chantal
通讯作者：
Sellier, Chantal
影响因子：
4.8
作者：
Figueroa, C;Tarras, S;Vojtek, AB
通讯作者：
Vojtek, AB
影响因子：
4.8
作者：
Lyons, Traci R.;Thorburn, Jackie;Kassenbrock, C. Kenneth
通讯作者：
Kassenbrock, C. Kenneth