# Astrocyte NLRP3 inflammasome activation in Parkinson's disease

> **NIH NIH F30** · JOHNS HOPKINS UNIVERSITY · 2020 · $50,520

## Abstract

Project Summary
Rapid population ageing portends dramatic increases in the prevalence of adult-onset neurodegenerative
disorders such as Parkinson’s disease (PD) in the coming decades. Inflammation, long considered an age-
associated epiphenomenon of neurodegeneration, has gradually been recast as a causal factor through newly
described neuroimmune disease mechanisms. Astrocytes are the predominant type of glial cell in the brain and
are induced by inflammatory cytokines to adopt a neurotoxic A1 reactive phenotype, which my PhD thesis lab
has linked to the degeneration of dopamine neurons in PD. However, the mechanisms by which A1 astrocytes
contribute to early events in PD pathogenesis, such as the pathologic aggregation of α-synuclein (αSyn),
remain undefined. Understanding these processes will clarify the value of A1 astrocytes as a therapeutic target
in early PD and may suggest novel roles in other neurodegenerative and neuroimmune disorders. My
preliminary data show that A1 astrocytes exhibit robust induction of the NLRP3 inflammasome, an effector of
the innate immune system recently implicated in αSyn aggregation. Furthermore, I have shown that primary
astrocyte cell cultures (1) can canonically activate the NLRP3 inflammasome, (2) readily internalize αSyn, and
(3) increase NLRP3 expression and IL-1β secretion in response to fibrillar αSyn aggregates, consistent with
inflammasome activation. Therefore, the central hypothesis of this proposal is that astrocyte NLRP3
inflammasome assembly can drive pathogenic αSyn aggregation, which in turn reinforces NLRP3 activation
and inflammation in PD. In Aim 1, we will determine whether the NLRP3 inflammasome promotes αSyn
aggregation in A1 astrocytes. In Aim 2, we will investigate astrocyte NLRP3 inflammasome activation by
exogenous αSyn fibrils. In Aim 3, we will demonstrate pathogenicity of astrocyte NLRP3 activation in the αSyn
preformed fibril (PFF) mouse model of PD. Primary astrocyte cultures will be used to establish the mechanistic
plausibility of this model in vitro. We will use transgenic and gene-targeted mice to selectively delete NLRP3 in
astrocytes and examine the impact on PD pathology in the αSyn PFF mouse model. Our research will identify
a novel mechanism by which A1 astrocytes contribute to early PD pathogenesis by promoting the aggregation
of αSyn into toxic species (Aim 1) and further show how αSyn can activate the potent NLRP3 inflammatory
cascade in astrocytes (Aim 2). We will also demonstrate that these processes have causal relevance in a well-
characterized PD mouse model (Aim 3). Collectively, this project will enhance our understanding of astrocytes
in PD etiology and characterize a novel disease role for the NLRP3 inflammasome. These studies comprise
the scientific context of my training plan as an MD/PhD student at Johns Hopkins, which will facilitate my
development as an independent physician-scientist. My sponsor, Ted Dawson, MD/PhD, is fully committed to
supporting my ...

## Key facts

- **NIH application ID:** 9990375
- **Project number:** 1F30AG067643-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Jared Hinkle
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 1
- **Project period:** 2020-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990375

## Citation

> US National Institutes of Health, RePORTER application 9990375, Astrocyte NLRP3 inflammasome activation in Parkinson's disease (1F30AG067643-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9990375. Licensed CC0.

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