Proteasome dysfunction induced by p-tau inhibits the cytoplasmic localization and function of HAS1 by blocking its monoubiquitylation.

Alzheimer's disease (AD) is a neurodegenerative disease with neuronal loss and
altered extracellular matrix (ECM) components. Here, we confirmed that both a
decreased high molecular hyaluronan (HMW-HA) and an increased low molecular
hyaluronan (LMW-HA) existed in AD mouse brains. The expression and distribution
patterns of the three types of hyaluronan synthases (HASs) were described in AD
mice. Immunofluorescence staining of AD mouse brain slices showed increased HAS1
and decreased HAS2 in the soma of neurons. In vitro data indicated that APP-induced
phosphorylated tau (p-tau) plays a key role in the reduction and redistribution of HAS1.
p-tau competitively inhibited the degradation of polyubiquitinated HAS1 (Ubn-HAS1) in
proteasomes, causing the accumulation of Ubn-HAS1 in the cytoplasm. As a
consequence of abnormal accumulation, accumulated Ubn-HAS1 was then subjected
to the lysosome degradation pathway, and unknown negative feedback loops were
activated to downregulate the transcription of HAS1 mRNA. Interestingly, the switch
between tau and p-tau modified the subcellular localization of HAS1 between the
cytoplasm and the nucleus by regulating the monoubiquitylation of HAS1 and
ultimately inhibited the synthesis and release of HMW-HA in neurons.

阿尔茨海默病（Alzheimer's disease，简称 AD）是一种神经退行性疾病，其特征为神经元减少和细胞外基质（ECM）成分的改变。在本研究中，我们证实了在 AD 小鼠脑中既存在高分子量透明质酸（HMW-HA）的减少，也存在低分子量透明质酸（LMW-HA）的增加。我们描述了 AD 小鼠中三种类型透明质酸合成酶（HASs）的表达和分布模式。对 AD 小鼠脑切片进行免疫荧光染色显示，HAS1 表达增加，而 HAS2 表达减少，主要发生在神经元胞体中。体外数据表明，由 APP 诱导的磷酸化tau（p-tau）在 HAS1 的减少和再分布中起着关键作用。p-tau 通过竞争性抑制多泛素化HAS1（Ubn-HAS1）在蛋白酶体中的降解，导致 Ubn-HAS1 在细胞质中的积累。由于这种异常积累，积累的 Ubn-HAS1 被置于溶酶体降解途径，并激活了未知的负反馈回路以下调 HAS1 mRNA 的转录。有趣的是，tau 与 p-tau 之间的转换通过调节 HAS1 的单泛素化，调节 HAS1 在细胞质和细胞核之间的亚细胞定位，最终抑制神经元中 HMW-HA 的合成和释放。