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.