Wiśniewska Karolina, Żabińska Magdalena, Gaffke Lidia, Szulc Aneta, Walter Beata M, Węgrzyn Grzegorz, Pierzynowska Karolina
Department of Molecular Biology, Faculty of Biology, University of Gdansk, 80-308 Gdansk, Poland.
Structural Biology Laboratory, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, 80-307 Gdansk, Poland.
Front Biosci (Landmark Ed). 2024 Dec 16;29(12):415. doi: 10.31083/j.fbl2912415.
Mucopolysaccharidosis (MPS) is a class of hereditary metabolic diseases that demonstrate itself by accumulating incompletely degraded glycosaminoglycans (GAGs). MPS are classified according to the kind(s) of stored GAG(s) and specific genetic/enzymatic defects. Despite the accumulation of the same type of GAG, two MPS diseases, Sanfilippo (MPS III) and Morquio (MPS IV), are further distinguished into subclasses based on different enzymes that are deficient. Although genetic defects in MPS are known, molecular mechanisms of particular MPS types are still incomplete. This work aimed to investigate gene expression patterns in MPS III and MPS IV subtypes to identify dysregulated genes that could indicate unidentified molecular mechanisms of the diseases.
Transcriptomic analyses were conducted to assess gene expression patterns in MPS and control cells. Western blotting and immunohistochemistry determined selected protein levels (products of the most significantly dysregulated genes). Effects of decreased levels of gene expression were investigated using small interferring RNA (siRNA)-mediated gene silencing.
Transcriptomic analyses indicated 45 commonly dysregulated genes among all MPS III subtypes and as many as 150 commonly dysregulated genes among both MPS IV subtypes. A few genes revealed particularly high levels of dysregulation, including , , and . Intriguingly, elevated levels of profilin-1 (product of the gene) could be reduced by decreasing GAG levels in genistein-treated MPS III and MPS IV cells, while silencing of caused a significant decrease in GAG accumulation in these cells, indicating an interdependent correlation between profilin-1 and GAG levels.
A plethora of commonly dysregulated genes were identified in MPS subtypes III and IV. Some of these genes, like , , and , revealed highly pronounced changes in expression relative to control cells. An interdependent correlation between GAG levels and the expression of the gene was identified. Thus, could be suggested as a potential new therapeutic target for MPS III and IV.
黏多糖贮积症（MPS）是一类遗传性代谢疾病，其特征是不完全降解的糖胺聚糖（GAGs）蓄积。MPS根据所储存的GAG种类和特定的遗传/酶缺陷进行分类。尽管储存的是同一类型的GAG，但两种MPS疾病，即Sanfilippo病（MPS III）和Morquio病（MPS IV），根据所缺乏的不同酶进一步分为不同亚类。虽然已知MPS中的遗传缺陷，但特定MPS类型的分子机制仍不完整。这项工作旨在研究MPS III和MPS IV亚型中的基因表达模式，以鉴定可能揭示疾病未知分子机制的失调基因。
进行转录组分析以评估MPS和对照细胞中的基因表达模式。蛋白质免疫印迹法和免疫组织化学法测定选定的蛋白质水平（最显著失调基因的产物）。使用小干扰RNA（siRNA）介导的基因沉默研究基因表达水平降低的影响。
转录组分析表明，所有MPS III亚型中有45个共同失调的基因，两种MPS IV亚型中有多达150个共同失调的基因。少数基因显示出特别高的失调水平，包括 、 和 。有趣的是，在染料木黄酮处理的MPS III和MPS IV细胞中，通过降低GAG水平可以降低原肌球蛋白-1（ 基因的产物）的升高水平，而沉默 会导致这些细胞中GAG蓄积显著减少，表明原肌球蛋白-1与GAG水平之间存在相互依赖的相关性。
在MPS III和IV亚型中鉴定出大量共同失调的基因。其中一些基因，如 、 和 ，相对于对照细胞显示出高度明显的表达变化。确定了GAG水平与 基因表达之间的相互依赖关系。因此， 可被认为是MPS III和IV的潜在新治疗靶点。
