As the backbone of the extracellular matrix (ECM) and the perineuronal nets (PNNs), hyaluronic acid (HA) provides binding sites for proteoglycans and other ECM components. Although the pivotal of HA has been recognized in Alzheimer's disease (AD), few studies have addressed the relationship between AD pathology and HA synthases (HASs). Here, HASs in different regions of AD brains were screened in transcriptomic database and validated in AβPP/PS1 mice. We found that HAS1 was distributed along the axon and nucleus. Its transcripts were reduced in AD patients and AβPP/PS1 mice. Phosphorylated tau (p-tau) mediates AβPP-induced cytosolic-nuclear translocation of HAS1, and negatively regulated the stability, monoubiquitination, and oligomerization of HAS1, thus reduced the synthesis and release of HA. Furthermore, non-ubiquitinated HAS1 mutant lost its enzyme activity, and translocated from the cytosol into the nucleus, forming nuclear speckles (NS). Unlike the splicing-related NS, less than 1 % of the non-ubiquitinated HAS1 co-localized with SRRM2, proving the regulatory role of HAS1 in gene transcription, indirectly. Thus, differentially expressed genes (DEGs) related to both non-ubiquitinated HAS1 mutant and AD were screened using transcriptomic datasets. Thirty-nine DEGs were identified, with 64.1 % (25/39) showing consistent results in both datasets. Together, we unearthed an important function of the AβPP-p-tau-HAS1 axis in microenvironment remodeling and gene transcription during AD progression, involving the ubiquitin-proteasome, lysosome, and NS systems.

中文翻译：

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AβPP-tau-HAS1 轴触发阿尔茨海默病中 HAS1 相关的核斑点和基因转录


作为细胞外基质 (ECM) 和神经周围网 (PNN) 的骨架，透明质酸 (HA) 为蛋白聚糖和其他 ECM 成分提供结合位点。尽管 HA 在阿尔茨海默病 (AD) 中发挥着关键作用，但很少有研究探讨 AD 病理学与 HA 合酶 (HAS) 之间的关系。在此，我们在转录组数据库中筛选了 AD 大脑不同区域的 HAS，并在 AβPP/PS1 小鼠中进行了验证。我们发现HAS1沿着轴突和细胞核分布。 AD 患者和 AβPP/PS1 小鼠中其转录本减少。磷酸化tau蛋白（p-tau）介导AβPP诱导的HAS1胞质核易位，负向调节HAS1的稳定性、单泛素化和寡聚化，从而减少HA的合成和释放。此外，非泛素化的HAS1突变体失去了酶活性，并从细胞质转移到细胞核中，形成核斑点（NS）。与剪接相关的 NS 不同，不到 1% 的非泛素化 HAS1 与 SRRM2 共定位，间接证明了 HAS1 在基因转录中的调节作用。因此，使用转录组数据集筛选与非泛素化 HAS1 突变体和 AD 相关的差异表达基因 (DEG)。确定了 39 个 DEG，其中 64.1% (25/39) 在两个数据集中显示出一致的结果。我们共同发现了 AβPP-p-tau-HAS1 轴在 AD 进展过程中微环境重塑和基因转录中的重要功能，涉及泛素蛋白酶体、溶酶体和 NS 系统。