Tomas Kavanagh, Kaleah Balcomb, Diba Ahmadi Rastegar, Guinevere F Lourenco, Thomas Wisniewski, Glenda Halliday, Eleanor Drummond
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引用次数: 0
摘要
Tau 与多种异质性核核糖核蛋白(hnRNPs)相互作用--这是一个 RNA 结合蛋白家族,可调控多种已知的细胞功能,包括 mRNA 剪接、mRNA 运输和翻译调控。我们之前已经证明了磷酸化 tau 与三种 hnRNPs(hnRNP A1、hnRNP A2B1 和 hnRNP K)之间特别重要的相互作用。虽然多种 hnRNPs 以前与 tau 病有牵连,但关于这些 hnRNPs 是否与 tau 聚集体共定位或在疾病中表现出细胞错定位的知识还很有限。在这里,我们进行了一项神经病理学研究,在六个疾病组(阿尔茨海默病、轻度认知障碍、进行性核上性麻痹、皮质基底变性、皮克氏病和对照组)的两个脑区(海马和额叶皮层)检测了 hnRNP A1、hnRNP A2B1、hnRNP K 和磷酸化 tau 之间的共定位。与预期相反,在所研究的任何一种牛磺酸病中,hnRNP A1、hnRNP A2B1 和 hnRNP K 均未与 AT8 免疫反应性磷酸化牛磺酸病理共聚焦。不过,我们确实观察到,在牛磺酸脑病中,hnRNP A1、hnRNP A2B1 和 hnRNP K 出现了明显的细胞错定位,每种 hnRNP 的错定位模式都各不相同。这些数据表明,在各种au病中,hnRNP A1、A2B1和K都出现了广泛的失调,对疾病过程和RNA调控产生了影响。
hnRNP A1, hnRNP A2B1, and hnRNP K are dysregulated in tauopathies, but do not colocalize with tau pathology.
Tau interacts with multiple heterogeneous nuclear ribonucleoproteins (hnRNPs)-a family of RNA binding proteins that regulate multiple known cellular functions, including mRNA splicing, mRNA transport, and translation regulation. We have previously demonstrated particularly significant interactions between phosphorylated tau and three hnRNPs (hnRNP A1, hnRNP A2B1, and hnRNP K). Although multiple hnRNPs have been previously implicated in tauopathies, knowledge of whether these hnRNPs colocalize with tau aggregates or show cellular mislocalization in disease is limited. Here, we performed a neuropathological study examining the colocalization between hnRNP A1, hnRNP A2B1, hnRNP K, and phosphorylated tau in two brain regions (hippocampus and frontal cortex) in six disease groups (Alzheimer's disease, mild cognitive impairment, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, and controls). Contrary to expectations, hnRNP A1, hnRNP A2B1, and hnRNP K did not colocalize with AT8-immunoreactive phosphorylated tau pathology in any of the tauopathies examined. However, we did observe significant cellular mislocalization of hnRNP A1, hnRNP A2B1 and hnRNP K in tauopathies, with unique patterns of mislocalization observed for each hnRNP. These data point to broad dysregulation of hnRNP A1, A2B1 and K across tauopathies with implications for disease processes and RNA regulation.
期刊介绍:
Brain Pathology is the journal of choice for biomedical scientists investigating diseases of the nervous system. The official journal of the International Society of Neuropathology, Brain Pathology is a peer-reviewed quarterly publication that includes original research, review articles and symposia focuses on the pathogenesis of neurological disease.