# Validating cGAS-STING pathway as drug target in Huntington disease mouse model

> **NIH NIH R21** · UNIVERSITY OF FLORIDA · 2022 · $531,300

## Abstract

Project summary
Huntington disease (HD) is a fatal neurodegenerative disorder caused by the huntingtin (HTT) CAG expansion
mutation (coding for polyglutamine, mHTT). mHTT is a ubiquitously expressed gene, yet it prominently damages
the striatum and cortex, followed by widespread peripheral defects as the disease progresses. Prior works have
linked innate and adaptive inflammatory responses in HD. Microglia, a cellular indicator of inflammation, is also
increased in the striatum of HD animal and cell culture models and HD patients. Increased levels of reactive
monocytes, inflammatory cytokines, chemokines, and the n-kynurenine/tryptophan ratio, an indicator of
persistent inflammation, have all been observed in pre-manifest HD patients and correlated with HD progression.
Furthermore, RNA-seq analysis of tissue obtained from human HD patients and HD monkey models reveals
extensive transcriptional dysregulation associated with proinflammatory pathway activation. Inflammation is also
closely linked to autophagy, a catabolic process that is dysregulated in HD. Despite these studies, the
mechanisms or treatment targets for the reduction of inflammatory responses remain less clear. To fill this
knowledge gap, this proposal tests the hypothesis that cyclic GMP–AMP synthase (cGAS)–stimulator of
interferon genes (STING), a major innate immunity response pathway, is a disease modifier in HD
pathogenesis. This hypothesis was formulated based on our recent finding that the cGAS-STING pathway is
upregulated in HD patients’ tissue and cell models and mediates autophagy and inflammatory responses. We
found high ribosome occupancy in exon 1 of cGAS mRNA and cGAS-dependent inflammatory transcription
factors (Irf3, Irf7), and inflammatory chemokine (Ccl5, and Cxcl10) are upregulated in HD. Depletion of cGAS
diminishes downstream effector STING activation and also inhibits autophagy flux in HD cells. The latter is
consistent with the primordial function of the cGAS-STING pathway in autophagy induction. These data underline
an important role of cGAS-STING signaling in the pathological mechanisms of HD. Subsequently, an
independent study confirmed activation of cGAS-STING in HD models. Yet, it is unclear whether the cGAS-
STING pathway is a passive or active contributor to HD development. In Aim 1, we will determine whether the
genetic deletion of cGAS alters the behavioral and pathological hallmarks of HD KI (z175HD) mice. We will
determine age-related behavioral alterations and pathological changes in cGAS–/–;HD KI mice. In Aim 2, we will
determine whether the small molecule STING inhibitor diminishes the HD phenotype in HD KI mice. We will treat
z175HD mice with the small molecule STING inhibitor, H-151 and determine changes in the HD-like deficits
compared vehicle treated z175HD. The proposed experiments will clarify the role of the cGAS–STING pathway
as anti-inflammatory therapeutic agents in HD.

## Key facts

- **NIH application ID:** 10508092
- **Project number:** 1R21NS128564-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Srinivasa Subramaniam
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $531,300
- **Award type:** 1
- **Project period:** 2022-09-20 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10508092

## Citation

> US National Institutes of Health, RePORTER application 10508092, Validating cGAS-STING pathway as drug target in Huntington disease mouse model (1R21NS128564-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10508092. Licensed CC0.

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