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Nuclear depletion of RNA-binding protein ELAVL3 (HuC) in sporadic and familial amyotrophic lateral sclerosis
Acta Neuropathologica ( IF 12.7 ) Pub Date : 2021-10-07 , DOI: 10.1007/s00401-021-02374-4
Sandra Diaz-Garcia 1 , Vivian I Ko 1 , Sonia Vazquez-Sanchez 2, 3 , Ruth Chia 4 , Olubankole Aladesuyi Arogundade 1 , Maria J Rodriguez 1 , Bryan J Traynor 4 , Don Cleveland 2, 3 , John Ravits 1
Affiliation  

Amyotrophic lateral sclerosis is a progressive fatal neurodegenerative disease caused by loss of motor neurons and characterized neuropathologically in almost all cases by nuclear depletion and cytoplasmic aggregation of TDP-43, a nuclear RNA-binding protein (RBP). We identified ELAVL3 as one of the most downregulated genes in our transcriptome profiles of laser captured microdissection of motor neurons from sporadic ALS nervous systems and the most dysregulated of all RBPs. Neuropathological characterizations showed ELAVL3 nuclear depletion in a great percentage of remnant motor neurons, sometimes accompanied by cytoplasmic accumulations. These abnormalities were common in sporadic cases with and without intermediate expansions in ATXN2 and familial cases carrying mutations in C9orf72 and SOD1. Depletion of ELAVL3 occurred at both the RNA and protein levels and a short protein isoform was identified, but it is not related to a TDP-43-dependent cryptic exon in intron 3. Strikingly, ELAVL3 abnormalities were more frequent than TDP-43 abnormalities and occurred in motor neurons still with normal nuclear TDP-43 present, but all neurons with abnormal TDP-43 also had abnormal ELAVL3. In a neuron-like cell culture model using SH-SY5Y cells, ELAVL3 mislocalization occurred weeks before TDP-43 abnormalities were seen. We interrogated genetic databases, but did not identify association of ELAVL3 genetic structure with ALS. Taken together, these findings suggest that ELAVL3 is an important RBP in ALS pathogenesis acquired early and the neuropathological data suggest that it is involved by loss of function rather than cytoplasmic toxicity.



中文翻译:

散发性和家族性肌萎缩侧索硬化症中 RNA 结合蛋白 ELAVL3 (HuC) 的核耗竭

肌萎缩侧索硬化症是一种进行性致命的神经退行性疾病,由运动神经元丧失引起,几乎所有病例的神经病理学特征是 TDP-43(一种核 RNA 结合蛋白 (RBP))的核耗竭和细胞质聚集。我们将 ELAVL3 鉴定为我们的转录组谱中最下调的基因之一,该基因来自散发性 ALS 神经系统的激光捕获显微切割运动神经元,并且是所有 RBP 中最失调的基因。神经病理学特征显示大部分残余运动神经元中的 ELAVL3 核耗竭,有时伴有细胞质积累。这些异常在伴有和不伴有 ATXN2 中间扩增的散发病例和携带 C9orf72 和 SOD1 突变的家族病例中很常见。在 RNA 和蛋白质水平都发生了 ELAVL3 的消耗,并且鉴定出一种短的蛋白质同种型,但它与内含子 3 中依赖于 TDP-43 的隐蔽外显子无关。引人注目的是,ELAVL3 异常比 TDP-43 异常更常见,并且发生在仍然存在正常核 TDP-43 的运动神经元中,但所有具有异常 TDP-43 的神经元也具有异常的 ELAVL3。在使用 SH-SY5Y 细胞的神经元样细胞培养模型中,ELAVL3 错误定位发生在 TDP-43 异常出现前几周。我们询问了遗传数据库,但没有确定 ELAVL3 遗传结构与 ALS 的关联。总之,这些发现表明 ELAVL3 是早期获得的 ALS 发病机制中的重要 RBP,并且神经病理学数据表明它与功能丧失而非细胞质毒性有关。

更新日期:2021-10-08
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