PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons
PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons
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DOI：
10.1038/s41593-024-01589-4
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发表时间：
2024-02-29
影响因子：
25
通讯作者：
Isaacs，Adrian M.
中科院分区：
文献类型：
--
作者：
Milioto，Carmelo;Carcole，Mireia;Isaacs，Adrian M.
二肽重复蛋白是C9 orf 72肌萎缩侧索硬化症（C9 ALS）/额颞叶痴呆（FTD）病理学的主要致病特征，但其生理影响尚未完全确定。在这里，我们产生了C9 orf 72二肽重复敲入小鼠模型，其特征是表达400个密码子优化的polyGR或polyPR重复，以及异源C9 orf 72减少。（GR）400和（PR）400基因敲入小鼠重现了C9 ALS/FTD的关键特征，包括皮质神经元过度兴奋、年龄依赖性脊髓运动神经元丢失和进行性运动功能障碍。定量蛋白质组学显示（GR）400和（PR）400脊髓细胞外基质（ECM）蛋白质增加，胶原蛋白COL 6A 1增加最多。TGF-β1是该ECM特征的最佳预测调节物之一，并且人诱导多能干细胞神经元中的polyGR表达足以诱导TGF-β1，然后是COL 6A 1。在polyGR模型中敲低TGF-β1或COL 6A 1直系同源物果蝇会加剧神经变性，而在C9 ALS/FTD患者的诱导多能干细胞衍生运动神经元中表达TGF-β1或COL 6A 1可防止谷氨酸诱导的细胞死亡。总之，我们的研究结果揭示了C9 ALS/FTD中神经保护和保守的ECM特征。
Dipeptide repeat proteins are a major pathogenic feature ofC9orf72amyotrophic lateral sclerosis (C9ALS)/frontotemporal dementia (FTD) pathology, but their physiological impact has yet to be fully determined. Here we generatedC9orf72dipeptide repeat knock-in mouse models characterized by expression of 400 codon-optimized polyGR or polyPR repeats, and heterozygousC9orf72reduction. (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 modelDrosophilaexacerbated 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.