PQBP1, a new player for brain inflammation under neurodegeneration, suggests that disease proteins are recognized as exogenous pathogens by microglia

Like Comment
Read the paper

Brain inflammation is a critical domain of pathologies in Alzheimer’s disease and other neurodegenerative diseases, and microglial activation promotes the brain inflammation. Recent studies from many groups are focusing on the role of microglia in Aβ and tau propagation from senile plaques (neuritic plaques), while the results are controversial on whether microglia are enhancing1 or preventing their propagation2,3. Gene mutations of TREM2, which is known as a cell membrane receptor of microglia for Aβ and possibly also for tau, are associated with late-onset Alzheimer’s disease as a risk factor4,5, while the pathological mechanisms are not completely disclosed. Meanwhile, TREM2 knockout mouse showed complicated phenotypes regarding Aβ pathology such as increased soluble and oligomer amyloid and decreased amyloid plaques at late stage6.

We added a new player, polyglutamine binding protein 1 (PQBP1), to the hot research topic of microglia in Alzheimer’s disease and other neurodegenerative diseases. PQBP1 was originally discovered as a binding protein to polyglutamine tract sequence to modify the pathology of polyglutamine diseases7–9. Retrospectively PQBP1 was one of the earliest discovered molecules having a character of intrinsically disordered protein (IDP) and showing the intracellular foci (not classical aggregation) based on liquid-liquid phase separation (LLPS)9,10, even before the discoveries of LLPS in TDP43 and FUS proteins.

In addition to the role in neurodegeneration, PQBP1 was shown to be a causative gene of multiple forms of human X-linked intellectual disability (ID)11–13. Moreover, in addition to the synapse maintenance function in neurons and the brain size regulating function in neural progenitor/stem cells14, PQBP1 has the third function as an intracellular receptor for exogenous pathogens like HIV virus in dendritic cell/macrophage15.

Knowledge of the interaction of PQBP1 with multiple neurodegenerative disease proteins and of the intracellular receptor function of PQBP1 in dendritic cells15 stimulated our imagination that PQBP1 might function in microglia, the dendritic cell in the brain, to sense neurodegenerative disease proteins. Our intensive analyses to examine this hypothesis supported that PQBP1 senses Tau 3R/4R proteins, especially their non-aggregated forms, as an exogenous pathogen to trigger brain inflammation (Figure 1)16.

Figure 1

The second point revealed from our study is functional relationship between the intracellular tau receptor PQBP1 and other cell surface receptors of microglia related to tau pathology like TREM2 and LRP1 (Figure 2). Our genetic analysis in this paper revealed that PQBP1 is in the downstream of LRP1 while not of TREM216. This seems to reconcile with the finding that tamoxifen-induced knockout of PQBP1 suppressed only a half of microglia in tau-induced activation16. LRP1-PQBP1 and TREM2 pathways are considered to function in parallel for tau-induced microglial activation. We identified that monomer rather than oligomer or polymer form of tau activates the PQBP1 pathway more effectively16. The preference of TREM2 for polymer form of tau17, 18 should also be considered in contrastive roles of the two pathways. Though TREM2 and PQBP1 play homologous roles in microglia, PQBP1 could not be a modifier gene of Alzheimer’s disease because it is a causative gene for human ID10–12 and the patients should be excluded from the cohort. However, further study would be necessary considering sex-differences of Alzheimer’s disease and tauopathy.

Figure 2

We are wondering how our new scheme would stimulate the research field. Given that PQBP1 might interact with other neurodegenerative disease proteins via WW or IDP domain, the scheme that PQBP1 senses a disease protein to induce brain inflammation from microglia could be applied to multiple neurodegenerative diseases including Huntington’s disease, spinocerebellar ataxia, and more other neurodegenerative diseases, in addition to Alzheimer’s disease and frontotemporal lobar degeneration associated with tau pathology (FTLD-tau). Huntingtin19 and ataxin19 are already known to interact with PQBP1.

 PQBP1 was originally discovered as a binding protein to polyglutamine-tract sequence of Brn2, a transcriptional factor regulating brain development. PQBP1 is expressed widely in various types of cells and tissues. Especially, the expressions in developmental and adult central nervous systems including neural stem cells and differentiated neurons are important, considering with the physiological function of PQBP1 in splicing of pre-mRNA from cell cycle genes and neuronal genes14, the pathological phenotypes like microcephaly and ID of human patients with PQBP1 gene mutations10–12, and the acquired dysfunction in Alzheimer’s disease pathology20 .

 PQBP1 plays dual functions in neuron and microglia, both of which contribute to neurodegenerative disease pathologies. Moreover, two different molecular pathways dependent on PQBP1 and TREM2 might explain controversial attitudes of microglia in Alzheimer’s disease and related dementias (Figure 3). We hope further studies of many research groups would solve the mystery.

Figure 3


  1. Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nature Neuroscience 18, 1584–1593 (2015).
  2. Yuan, P. et al. TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy. Neuron 90, 724–739 (2016).
  3. Wang, Y. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. Journal of Experimental Medicine 213, 667–675 (2016).
  4. Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. New England Journal of Medicine 368, 117–127 (2013).
  5. Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. New England Journal of Medicine 368, 107–116 (2013).
  6. Meilandt, W. J. et al. TREM2 deletion reduces late-stage amyloid plaque accumulation, elevates the Aβ42:Aβ40 ratio, and exacerbates axonal dystrophy and dendritic spine loss in the PS2ApP Alzheimer’s mouse model. Journal of Neuroscience 40, 1956–1974 (2020).
  7. Imafuku, I. et al. Polar amino acid-rich sequences bind to polyglutamine tracts. Biochemical and Biophysical Research Communications 253, 16–20 (1998).
  8. Waragai, M. et al. PQBP-1, a novel polyglutamine tract-binding protein, inhibits transcription activation by Brn-2 and affects cell survival. Human Molecular Genetics 8, 977–987 (1999).
  9. Okazawa, H. et al. Interaction between mutant ataxin-1 and PQBP-1 affects transcription and cell death. Neuron 34, 701–713 (2002).
  10. Okazawa, H., Sudol, M. & Rich, T. PQBP-1 (Np/PQ): a polyglutamine tract-binding and nuclear inclusion-forming protein. Brain Research Bulletin 56, 273–280 (2001).
  11. Kalscheuer, V. M. et al. Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation. Nature Genetics 35, 313–315 (2003).
  12. Lenski, C. et al. Novel Truncating Mutations in the Polyglutamine Tract Binding Protein 1 Gene (PQBP1) Cause Renpenning Syndrome and X-Linked Mental Retardation in Another Family with Microcephaly. American Journal of Human Genetics 74, 777–780 (2004).
  13. Stevenson, R. E. et al. Renpenning syndrome comes into focus. American Journal of Medical Genetics 134 A, 415–421 (2005).
  14. Ito, H. et al. In utero gene therapy rescues microcephaly caused by Pqbp1-hypofunction in neural stem progenitor cells. Molecular Psychiatry 20, 459–471 (2015).
  15. Yoh, S. M. et al. PQBP1 is a proximal sensor of the cGAS-dependent innate response to HIV-1. Cell 161, 1293–1305 (2015).
  16. Jin, M. et al. Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation. Nature Communications 12, 6565 (2021).
  17. Leyns, C. E. G. et al. TREM2 function impedes tau seeding in neuritic plaques. Nature Neuroscience 22, 1217–1222 (2019).
  18. Lee, S.-H. et al. Trem2 restrains the enhancement of tau accumulation and neurodegeneration by b-amyloid pathology. Neuron 109, 1283-1301.e6 (2021).
  19. Busch, A. et al. Mutant huntingtin promotes the fibrillogenesis of wild-type huntingtin: A potential mechanism for loss of huntingtin function in Huntington’s disease. Journal of Biological Chemistry 278, 41452–41461 (2003).
  20. Tanaka, H. et al. The intellectual disability gene PQBP1 rescues Alzheimer’s disease pathology. Mol Psychiatry 23, 2090–2110 (2018).


Professor and Chair, Tokyo Medical and Dental University