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首页> 外文期刊>Cellular Signalling >Comparative transcriptomics reveals mechanisms underlying cln3-deficiency phenotypes in Dictyostelium
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Comparative transcriptomics reveals mechanisms underlying cln3-deficiency phenotypes in Dictyostelium

机译：比较转录组织揭示了Dictyostelium中Cln3缺乏表型的机制

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摘要

Mutations in CLN3 cause a juvenile form of neuronal ceroid lipofuscinosis (NCL). This devastating neurological disorder, commonly known as Batten disease, is currently untreatable due to a lack of understanding of the physiological role of the protein. Recently, work in the social amoeba Dictyostelium discoideum has provided valuable new insight into the function of CLN3 in the cell. More specifically, research has linked the Dictyostelium homolog (gene: cln3, protein: Cln3) to protein secretion, adhesion, and aggregation during starvation, which initiates multicellular development. In this study, we used comparative transcriptomics to explore the mechanisms underlying the aberrant response of cln3(-) cells to starvation. During starvation, 1153 genes were differentially expressed in cln3(-) cells compared to WT. Among the differentially expressed genes were homologs of other human NCL genes including TPP1/CLN2, CLN5, CTSD/CLN10, PGRN/CLN11, and CTSF/CLN13. STRING and GO term analyses revealed an enrichment of genes linked to metabolic, biosynthetic, and catalytic processes. We then coupled the findings from the RNA-seq analysis to biochemical assays, specifically showing that loss of cln3 affects the expression and activity of lysosomal enzymes, increases endo-lysosomal pH, and alters nitric oxide homeostasis. Finally, we show that cln3(-) cells accumulate autofluorescent storage bodies during starvation and provide evidence linking the function of Cln3 to Tpp1 and CtsD activity. In total, this study enhances our knowledge of the molecular mechanisms underlying Cln3 function in Dictyostelium.
机译：ClN3中的突变导致幼年形态的神经元曲线痘痘（NCL）。这种毁灭性的神经疾病，通常被称为肉豆疾病，目前是无法治愈的，因为缺乏对蛋白质的生理作用的理解。最近，在社交Amoeba dictyostelium discoide中的工作已经为Cln3在细胞中提供了有价值的新洞察力。更具体地，研究将Dictyostelium同源物（基因：ClN3，蛋白质：ClN3）与蛋白质分泌，粘附性和聚集联系在饥饿期间，引发多细胞发育。在这项研究中，我们使用比较转录组科探讨ClN3（ - ）细胞对饥饿的异常响应的机制。在饥饿期间，与WT相比，1153个基因在ClN3（ - ）细胞中差异表达。在差异表达的基因中，包括其他人NCL基因的同源物，包括TPP1 / CLN2，CLN5，CTSD / CLN10，PGRN / CLN11和CTSF / CLN13。字符串和转入术语分析显示与代谢，生物合成和催化过程相关的基因的富集。然后，从RNA-SEQ分析偶联对生物化学测定的结果，具体表明CLN3的损失影响溶酶体酶的表达和活性，增加了内泌体pH，并改变了一氧化氮稳态。最后，我们表明CLN3（ - ）细胞在饥饿期间累积自发荧光存储体，并提供将CLN3功能与TPP1和CTSD活动的证据。本研究总共增强了我对Dictyostelium中CLN3功能的分子机制的了解。

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