小柯机器人

英国伦敦大学学院Adrian M. Isaacs等研究人员合作发现，polyGR和polyPR基因敲入小鼠揭示C9orf72 ALS/FTD神经元中具有神经保护作用的细胞外基质特征。相关论文于2024年2月29日在线发表在《自然—神经科学》杂志上。

研究人员生成了C9orf72二肽重复基因敲入小鼠模型，其特征是表达400个密码子优化的polyGR或polyPR重复序列，以及杂合子C9orf72减少。(GR)400和(PR)400基因敲入小鼠再现了C9orf72肌萎缩侧索硬化症（C9ALS）/颞前痴呆症（FTD）的主要特征，包括皮层神经元过度兴奋、年龄依赖性脊髓运动神经元缺失和进行性运动功能障碍。定量蛋白质组学发现，(GR)400和(PR)400脊髓中细胞外基质（ECM）蛋白增加，其中胶原蛋白COL6A1增加最多。

TGF-β1是这种ECM特征的首要预测调节因子之一，在人类诱导多能干细胞神经元中表达polyGR足以诱导TGF-β1，其次是COL6A1。在polyGR模型果蝇中敲除TGF-β1或COL6A1同源物会加剧神经退行性变，而在C9ALS/FTD患者的诱导多能干细胞衍生运动神经元中表达TGF-β1或COL6A1则能防止谷氨酸诱导的细胞死亡。总之，这些研究结果揭示了C9ALS/FTD种的神经保护作用和保守的ECM特征。

据介绍，二肽重复蛋白是C9ALS/FTD病理的主要致病特征，但其生理影响尚未完全确定。

附：英文原文

Title: PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons

Author: Milioto, Carmelo, Carcol, Mireia, Giblin, Ashling, Coneys, Rachel, Attrebi, Olivia, Ahmed, Mhoriam, Harris, Samuel S., Lee, Byung Il, Yang, Mengke, Ellingford, Robert A., Nirujogi, Raja S., Biggs, Daniel, Salomonsson, Sally, Zanovello, Matteo, de Oliveira, Paula, Katona, Eszter, Glaria, Idoia, Mikheenko, Alla, Geary, Bethany, Udine, Evan, Vaizoglu, Deniz, Anoar, Sharifah, Jotangiya, Khrisha, Crowley, Gerard, Smeeth, Demelza M., Adams, Mirjam L., Niccoli, Teresa, Rademakers, Rosa, van Blitterswijk, Marka, Devoy, Anny, Hong, Soyon, Partridge, Linda, Coyne, Alyssa N., Fratta, Pietro, Alessi, Dario R., Davies, Ben, Busche, Marc Aurel, Greensmith, Linda, Fisher, Elizabeth M. C., Isaacs, Adrian M.

Issue&Volume: 2024-02-29

Abstract: Dipeptide repeat proteins are a major pathogenic feature of C9orf72 amyotrophic lateral sclerosis (C9ALS)/frontotemporal dementia (FTD) pathology, but their physiological impact has yet to be fully determined. Here we generated C9orf72 dipeptide repeat knock-in mouse models characterized by expression of 400 codon-optimized polyGR or polyPR repeats, and heterozygous C9orf72 reduction. (GR)400 and (PR)400 knock-in mice recapitulate key features of C9ALS/FTD, including cortical neuronal hyperexcitability, age-dependent spinal motor neuron loss and progressive motor dysfunction. Quantitative proteomics revealed an increase in extracellular matrix (ECM) proteins in (GR)400 and (PR)400 spinal cord, with the collagen COL6A1 the most increased protein. TGF-β1 was one of the top predicted regulators of this ECM signature and polyGR expression in human induced pluripotent stem cell neurons was sufficient to induce TGF-β1 followed by COL6A1. Knockdown of TGF-β1 or COL6A1 orthologues in polyGR model Drosophila exacerbated neurodegeneration, while expression of TGF-β1 or COL6A1 in induced pluripotent stem cell-derived motor neurons of patients with C9ALS/FTD protected against glutamate-induced cell death. Altogether, our findings reveal a neuroprotective and conserved ECM signature in C9ALS/FTD.

DOI: 10.1038/s41593-024-01589-4

Source: https://www.nature.com/articles/s41593-024-01589-4

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex