# Targeting Innate Immunity as A Therapeutic Intervention for Parkinsons Disease

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2023 · —

## Abstract

This proposal is a renewal of our current VA Merit award and is focused on understanding the interactions
between innate immune responses and Parkinson’s Disease (PD) pathogenesis. We previously discovered
that the neuronal protein, alpha-synuclein (α-syn), protects the brain from viral infections. With our current VA
Merit support, we extended these findings to discover that α-syn expression in neurons is required for
expression of neuronal interferon stimulated gene (ISG) expression independent of microglial activation during
acute viral infection in the brain. Loss of neuron-specific expression of α-syn results in increased virus growth
in primary human neurons and decreased activation of infiltrating cytotoxic T-cell responses. We extended
these findings to show that stimulation of specific RNA sensing and signaling pathways within neurons
activates ISGs in an α-syn-dependent mechanism. Our current mechanistic studies form the foundation for the
current proposal.
 For the next phase of our work and the subject of the current VA merit award application, we want to
understand the role of α-syn-dependent innate immune responses in progression of PD neuropathology. Our
fundamental hypothesis is that PD is an innate immune disorder and that inhibition of specific innate immune
pathways associated with α-syn-dependent innate immune responses will inhibit the progression of PD
pathology.
 The Brundin laboratory, our collaborator, has developed a murine model of prodromal PD that
recapitulates the spread of α-syn pathology from the olfactory bulb to the midbrain in mice. This proposal
combines this disease relevant model with approaches for targeted knockout or stimulation of specific innate
immune responses to determine the effect on propagation of α-syn pathology, neurodegeneration, and
inflammatory responses in the brain. The three independent, related aims will provide novel insight into a
potential disease-modifying therapeutic intervention for PD.
 The first aim will use target gene knockout of specific innate immune genes to determine the role of
specific innate immune pathways on the progression of PD pathology. The second aim will use targeted
stimulation of select innate immune pathways and evaluate the effect on PD pathology. The third aim will
employ inhibitory antibodies for specific innate immune pathways and determine the role of antibody-mediated
inhibition of selected innate immune pathways on the progression of PD pathology. If the studies are
completed as outlined, we will identify potential disease modifying targets for the treatment of PD.

## Key facts

- **NIH application ID:** 10695873
- **Project number:** 5I01BX003863-07
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** John David Beckham
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-07-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10695873

## Citation

> US National Institutes of Health, RePORTER application 10695873, Targeting Innate Immunity as A Therapeutic Intervention for Parkinsons Disease (5I01BX003863-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10695873. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*