# The Role of Striatal Astrocytic Dopamine D2 Receptor Signaling in the Pathogenesis of LRRK2-Mediated Parkinson's Disease

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2024 · $237,160

## Abstract

Mutations on the LRRK2 gene, which increase the encoded protein's kinase activity, are common genetic causes
of familial Parkinson's disease (PD). Noncoding variants at the LRRK2 locus have also been linked to an
increased risk of sporadic PD. Thus, LRRK2 is a promising therapeutic target in familial and sporadic PD. While
small molecule LRRK2 kinase inhibitors are currently tested in clinical trials, the precise pathological
mechanisms of LRRK2 mutations remain unknown. Several studies have supported the idea of non-cell
autonomous mechanisms leading to DA neuron death, a pathological PD hallmark. We observed elevated
astrogliosis in the caudate/putamen of postmortem LRRK2G2019S carriers and LRRK2G2019S knockin mice.
Together with a well-accepted role of LRRK2 in synapse and inflammation, this suggests that aberrant LRRK2
kinase activity increases the inflammatory burden in the nigrostriatal synapse by involving astrocytic activation.
A limited understanding of the astrocyte signaling pathways relevant to PD hampered progress in establishing
astrocyte dysfunction with PD pathophysiology. As our findings show a role of LRRK2 in the dopamine D2
receptor (D2R) signaling in the striatal astrocytes, the overarching goal of this study is to link astrocytic LRRK2-
mediated D2R signaling impairments to neuroinflammation in these mice representing prodromal PD. Overall,
we aim to explore if LRRK2-mediated striatal astrocyte D2R signaling perturbations exacerbate early synaptic
inflammatory processes that lead to PD.
We will utilize innovative genetic models and viral approaches to manipulate D2R signaling in identified
astrocytes, allowing us to dissect D2R signaling-mediated mechanisms with high specificity in a specific cell type
manner.
Aim 1 will mechanistically link impaired D2R signaling and inflammation in striatal LRRK2G2019S astrocytes.
In Aim 2, we will manipulate D2R signaling specific in striatal astrocytes and assess how this influences
inflammation, neurotoxicity, and behavior in vivo.
In light of the clinical testing of small molecule inhibitors against LRRK2 kinase and D2R agonists in the clinical
setting, our work is crucially placed to set the framework for developing disease-modifying strategies targeting
astrocyte dopamine signaling in the striatum.

## Key facts

- **NIH application ID:** 10991541
- **Project number:** 1R21AG089563-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Loukia Parisiadou
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $237,160
- **Award type:** 1
- **Project period:** 2024-08-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10991541

## Citation

> US National Institutes of Health, RePORTER application 10991541, The Role of Striatal Astrocytic Dopamine D2 Receptor Signaling in the Pathogenesis of LRRK2-Mediated Parkinson's Disease (1R21AG089563-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10991541. Licensed CC0.

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