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首页> 外文期刊>The European Journal of Neuroscience >Identification of biological pathways regulated by PGRN and GRN peptide treatments using transcriptome analysis
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Identification of biological pathways regulated by PGRN and GRN peptide treatments using transcriptome analysis

机译：使用转录组分析鉴定受PGRN和GRN肽治疗调节的生物途径

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Mutations in progranulin (PGRN) have been linked to two neurodegenerative disorders, heterozygote mutations with frontotemporal lobar degeneration (FTLD) and homozygote mutations with neuronal ceroid lipofuscinosis (NCL). Human PGRN is 593aa secreted growth factor, made up of seven and a half repeats of a highly conserved granulin motif that is cleaved to produce the granulin peptides A-G and paragranulin. While it is thought that PGRN protects against neurodegeneration through its role in inflammation and tissue repair, the role of PGRN and granulins in the nervous system is currently unclear. To better understand this, we prepared recombinant PGRN, granulin A-F and paragranulin, and used these to treat differentiated neuronal SH-SY5Y cells. Using RNA sequencing and bioinformatics techniques we investigated the functional effects of PGRN and the individual granulins upon the transcriptome. For PGRN treatment we show that the main effect of short-duration treatments is the down-regulation of transcripts, supporting that signalling pathway induction appears to be dominant effect. Gene ontology analysis, however, also supports the regulation of biological processes such as the spliceosome and proteasome in response to PGRN treatment, as well as the lysosomal pathway constituents such as CHMP1A, further supporting the role of PGRN in lysosomal function. We also show that the response to granulin treatments involves the regulation of numerous non-coding RNA's, and the granulins cluster into groups of similar activity on the basis of expression profile with paragranulin and PGRN having similar expression profiles, while granulins B, D, E and G appear more similar.
机译：前颗粒蛋白（PGRN）的突变与两种神经退行性疾病有关，即额颞叶变性（FTLD）的杂合子突变和神经元类脂褐藻病（NCL）的纯合子突变。人PGRN是593aa分泌的生长因子，由高度保守的颗粒蛋白基序的七个半重复组成，该基序被切割以产生颗粒蛋白肽A-G和副颗粒蛋白。尽管人们认为PGRN通过其在炎症和组织修复中的作用来防止神经退行性变，但目前尚不清楚PGRN和颗粒蛋白在神经系统中的作用。为了更好地理解这一点，我们制备了重组PGRN，颗粒蛋白A-F和副颗粒蛋白，并将其用于治疗分化的神经元SH-SY5Y细胞。使用RNA测序和生物信息学技术，我们调查了PGRN和单个颗粒蛋白对转录组的功能作用。对于PGRN治疗，我们表明短期治疗的主要作用是转录物的下调，支持信号传导途径的诱导似乎是主要作用。但是，基因本体分析还支持对PGRN处理做出反应的生物过程（例如剪接体和蛋白酶体）的调节，以及溶酶体途径的成分（例如CHMP1A），进一步支持PGRN在溶酶体功能中的作用。我们还表明，对颗粒蛋白治疗的反应涉及许多非编码RNA的调节，并且颗粒蛋白根据表达谱与聚粒蛋白和PGRN具有相似表达谱的聚类成类似活性的组，而颗粒蛋白B，D，E和G看起来更相似。

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