Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, 1 Wakefield Street, London, WC1N 1PJ, UK.
Acta Neuropathol Commun. 2019 Feb 12;7(1):18. doi: 10.1186/s40478-019-0673-y.
Frontotemporal lobar degeneration (FTLD) is pathologically subdivided based on the presence of particular pathological proteins that are identified in inclusion bodies observed post-mortem. The FTLD-FUS subgroup is defined by the presence of the fused in sarcoma protein (FUS) in pathological inclusions. FUS is a heterogeneous nuclear ribonucleoprotein (hnRNP) protein and a member of the FET (FUS, EWS, TAF15) protein family. It shuttles between the nucleus and cytoplasm, and has been implicated in many cellular functions including translation, splicing, and RNA transport. EWS, TAF15 and the nuclear import receptor transportin have been shown to co-accumulate with FUS in neuronal inclusions specifically in FTLD-FUS, with transportin-positive inclusions most frequently observed. Here, we report the identification of hnRNP R and hnRNP Q in neuronal cytoplasmic and intranuclear inclusions in the frontal cortex and hippocampus of FTLD-FUS patients, as frequently as transportin. hnRNP R and hnRNP Q were not found in the characteristic pathological inclusions observed in FTLD-TDP (subtypes A-C). Additionally, we studied the expression of hnRNP R in the frontal and temporal cortices from patients with FTLD and found significantly increased expression of the heterogeneous nuclear ribonucleoprotein R in several FTLD disease groups. Our identification of the frequent presence of hnRNP R and hnRNP Q in FTLD-FUS inclusions suggests a potential role for these hnRNPs in FTLD-FUS pathogenesis and supports the role of dysfunctional RNA metabolism in FTLD.
额颞叶变性（FTLD）基于在死后观察到的包含体中存在特定的病理蛋白进行病理细分。FTLD-FUS 亚组的定义是存在融合肉瘤蛋白（FUS）在病理包含物中。FUS 是一种异质核核糖核蛋白（hnRNP）蛋白，也是 FET（FUS、EWS、TAF15）蛋白家族的成员。它在核和细胞质之间穿梭，参与许多细胞功能，包括翻译、剪接和 RNA 运输。已经表明 EWS、TAF15 和核输入受体 transportin 与 FUS 在神经元包含物中共同积累，特别是在 FTLD-FUS 中，最常观察到 transportin 阳性包含物。在这里，我们报告了 hnRNP R 和 hnRNP Q 在 FTLD-FUS 患者额皮质和海马的神经元细胞质和核内包含物中的鉴定，其频率与 transportin 相同。hnRNP R 和 hnRNP Q 未在 FTLD-TDP（亚型 A-C）中观察到的特征性病理包含物中发现。此外，我们研究了 FTLD 患者额叶和颞叶皮质中 hnRNP R 的表达，发现几种 FTLD 疾病组中 hnRNP R 的表达显著增加。我们发现 hnRNP R 和 hnRNP Q 在 FTLD-FUS 包含物中频繁存在，这表明这些 hnRNPs 在 FTLD-FUS 发病机制中具有潜在作用，并支持 RNA 代谢功能障碍在 FTLD 中的作用。
