Abstract
Brain inflammation generally accompanies and accelerates neurodegeneration. Here we report a microglial mechanism in which polyglutamine binding protein 1 (PQBP1) senses extrinsic tau 3R/4R proteins by direct interaction and triggers an innate immune response by activating a cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) pathway. Tamoxifen-inducible and microglia-specific depletion of PQBP1 in primary culture in vitro and mouse brain in vivo shows that PQBP1 is essential for sensing-tau to induce nuclear translocation of nuclear factor κB (NFκB), NFκB-dependent transcription of inflammation genes, brain inflammation in vivo, and eventually mouse cognitive impairment. Collectively, PQBP1 is an intracellular receptor in the cGAS-STING pathway not only for cDNA of human immunodeficiency virus (HIV) but also for the transmissible neurodegenerative disease protein tau. This study characterises a mechanism of brain inflammation that is common to virus infection and neurodegenerative disorders.
Highlights
Yuki Yoshioka 1, Xiaocen Jin 1, Kanoh Kondo 1, Kyota Fujita 1, Hidenori Homma 1, Kazuyuki Nakajima 4, Mineyuki Mizuguchi 3 & Hitoshi Okazawa 1✉
In addition to the sensing mechanisms by cell surface receptors for extracellular and intercellular proteins, these results show a third mechanism of inflammation in the brain of neurodegenerative diseases by an intracellular receptor, which could be generalized to multiple diseases since interaction rather than co-aggregation between the disease protein and PQBP1 occurs in Huntington’s disease (HD) and spinocerebellar ataxia type 1 (SCA1)[12,13,41]
Surface plasmon resonance (SPR) analysis revealed that Tau 410 and Tau 441 full-length proteins almost interacted with WW domain (WWD) of PQBP1 (Fig. 1b and Supplementary Table 1)
Summary
Yuki Yoshioka 1, Xiaocen Jin 1, Kanoh Kondo 1, Kyota Fujita 1, Hidenori Homma 1, Kazuyuki Nakajima 4, Mineyuki Mizuguchi 3 & Hitoshi Okazawa 1✉. We report a microglial mechanism in which polyglutamine binding protein 1 (PQBP1) senses extrinsic tau 3R/4R proteins by direct interaction and triggers an innate immune response by activating a cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) pathway. PQBP1 is an intracellular receptor in the cGAS-STING pathway for cDNA of human immunodeficiency virus (HIV) and for the transmissible neurodegenerative disease protein tau. This study characterises a mechanism of brain inflammation that is common to virus infection and neurodegenerative disorders. Neurodegenerative diseases are associated with inflammation of the brain[1]. Extracellular disease proteins like Aβ2 and damage-associated molecular patterns (DAMPs) such as high mobility group box protein 1 (HMGB1) or Aβ3,4 released from sick neurons are the first group of stimuli for activating.
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