Entorhinal cortical neurons are the primary targets of FUS mislocalization and ubiquitin aggregation in FUS transgenic rats
Entorhinal cortical neurons are the primary targets of FUS mislocalization and ubiquitin aggregation in FUS transgenic rats
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DOI：
10.1093/hmg/dds299
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发表时间：
2012-11-01
影响因子：
3.5
通讯作者：
Xia, Xu-Gang
中科院分区：
文献类型：
--
作者：
Huang, Cao;Tong, Jianbin;Xia, Xu-Gang
融合肉瘤（FUS）是一种新的额颞叶变性（FTLD）亚型。FTLD的特征是认知功能的进行性改变，并且它优先影响额颞叶皮层的浅层。FUS突变与肌萎缩侧索硬化症和运动神经元疾病伴FTLD有关。为了检查FTLD中的FUS病理，我们开发了第一个表达具有致病性突变的人FUS并发展为进行性记忆丧失的哺乳动物模型。在FUS转基因大鼠中，泛素聚集和FUS错误定位主要发生在颞叶的内嗅皮层，特别是在受累皮层的浅层。过量表达突变型FUS导致高尔基体断裂和高尔基体聚集。有趣的是，聚集的泛素没有与片段化的高尔基体或聚集的线粒体共定位，并且具有泛素聚集体的神经元被剥夺了内源性TDP-43。过氧化物酶体增殖物激活受体γ（PPAR-）的激动剂具有抗神经胶质炎症作用，并且还显示出在培养中保留皮质神经元的树突和树突棘。在这里，我们发现罗格列酮，一种过氧化物酶体增殖体激活物受体激动剂，从FUS毒性中拯救神经元的树突和树突棘，并保护大鼠的空间记忆。FUS转基因大鼠为进一步研究FTLD皮质性痴呆的发病机制奠定了基础。由于罗格列酮在临床上用于治疗糖尿病，我们的结果将鼓励立即应用过氧化物酶体增殖物激活物受体激动剂治疗皮质性痴呆患者。
Ubiquitin-positive inclusion containing Fused in Sarcoma (FUS) defines a new subtype of frontotemporal lobar degeneration (FTLD). FTLD is characterized by progressive alteration in cognitions and it preferentially affects the superficial layers of frontotemporal cortex. Mutation of FUS is linked to amyotrophic lateral sclerosis and to motor neuron disease with FTLD. To examine FUS pathology in FTLD, we developed the first mammalian animal model expressing human FUS with pathogenic mutation and developing progressive loss of memory. In FUS transgenic rats, ubiquitin aggregation and FUS mislocalization were developed primarily in the entorhinal cortex of temporal lobe, particularly in the superficial layers of affected cortex. Overexpression of mutant FUS led to Golgi fragmentation and mitochondrion aggregation. Intriguingly, aggregated ubiquitin was not colocalized with either fragmented Golgi or aggregated mitochondria, and neurons with ubiquitin aggregates were deprived of endogenous TDP-43. Agonists of peroxisome proliferator-activated receptor gamma (PPAR-) possess anti-glial inflammation effects and are also shown to preserve the dendrite and dendritic spines of cortical neurons in culture. Here we show that rosiglitazone, a PPAR- agonist, rescued the dendrites and dendritic spines of neurons from FUS toxicity and preserved rats spatial memory. Our FUS transgenic rats would be useful to the mechanistic study of cortical dementia in FTLD. As rosiglitazone is clinically used to treat diabetes, our results would encourage immediate application of PPAR- agonists in treating patients with cortical dementia.