# PQBP1 as a central regulator of inflammation in neurodegenerative diseases

> **NIH NS F31** · SCRIPPS RESEARCH INSTITUTE, THE · 2026 · $37,114

## Abstract

PROJECT SUMMARY:
Neurodegenerative diseases pose significant challenges to public health and our understanding of brain function.
Central to these conditions is the pathological accumulation of protein aggregates, notably alpha-synuclein, beta-
amyloid, and Tau. Specifically, Tau aggregates are expelled into the extracellular space as neurons degenerate,
where they act as damage-associated molecular patterns (DAMPs) that are sensed by microglia. Microglial
activation leads to inflammatory responses, which contribute to impaired neuronal function and cognitive decline
in diseases like Alzheimer’s Disease (AD). Although various pattern recognition receptors (PRRs) have been
reported to sense Tau, emerging evidence suggests that cyclic cGAMP synthase (cGAS), a DNA PRR, also
plays a crucial role in promoting inflammatory responses. Recent reports suggest that Tau activates the cGAS
pathway, and this would require an initial interaction with an adaptor, Polyglutamate Binding Protein 1 (PQBP1).
In three separate studies, our group has shown a similar requirement for cGAS activation by HIV-1 infection.
PQBP1 decorates HIV-1 capsids and recruits cGAS to the site of HIV-1 DNA synthesis. PQBP1 recruitment to
the capsid is mediated by charge complementation, and its dimerization is required for cGAS activation. We
hypothesize that PQBP1 binding to Tau is necessary for cGAS activation, which contributes to chronic
neuroinflammation in AD and other tauopathies. Building on our experience and reagents from our HIV-1 studies
on PQBP1 and cGAS, we propose to fill major gaps in knowledge regarding the structural requirements of
PQBP1-Tau complex formation and its contribution to cGAS activation. In Aim 1, we will determine the regions
of PQBP1 that are required for the recognition of Tau monomers and fibrils. Further, we will elucidate whether
PQBP1 interacts with exogenous PQBP1 as well as PQBP1 expressed in microglia. In Aim 2, we will
demonstrate that the cGAS pathway is active i

## Key facts

- **NIH application ID:** 11375831
- **Project number:** 5F31NS141616-02
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Dale S Allen
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NS
- **Fiscal year:** 2026
- **Award amount:** $37,114
- **Award type:** 5
- **Project period:** 2025-02-01T00:00:00 → 2029-01-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11375831

## Citation

> US National Institutes of Health, RePORTER application 11375831, PQBP1 as a central regulator of inflammation in neurodegenerative diseases (5F31NS141616-02). Retrieved via AI Analytics 2026-07-12 from https://api.ai-analytics.org/grant/nih/11375831. Licensed CC0.

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