# Clinically advanced NLRP3 inhibitor modulates microglial transcriptome and alleviates α-synuclein-induced progression of parkinsonism

## TL;DR

A drug that inhibits NLRP3 reduces brain inflammation and slows Parkinson's-like symptoms in animal models by reprogramming microglia and lowering harmful biomarkers.

## Contribution

Demonstrates dapansutrile's ability to reverse microglial gene expression linked to Parkinson's and MSA, with translational biomarkers for treatment monitoring.

## Key findings

- Chronic dapansutrile treatment reduced α-synuclein inclusions and neurodegeneration in mouse models of Parkinson's and MSA.
- Dapansutrile reversed disease-associated microglial transcriptional signatures in the brain.
- Plasma IL-18 and NfL levels correlated with treatment efficacy and neuropathological outcomes.

## Abstract

Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease, and the rare disorder multiple system atrophy (MSA), are both characterized by intracellular accumulation of α-synuclein fibrils and early, sustained microglial reactivity in parallel to the neurodegeneration. Activation of the NLRP3 inflammasome in disease-associated reactive microglia is increasingly recognized as a key pathogenic driver and a promising therapeutic target in synucleinopathies. Dapansutrile (OLT1177®) is a selective, orally bioavailable NLRP3 inhibitor with a favorable safety profile in clinical trials for non-neurological indications. Here, we evaluated the therapeutic potential of dapansutrile in preclinical models of PD and MSA and explored the predictive and translational value of its effects.

Two established mouse models of synucleinopathy with nigral neurodegeneration were employed: the α-synuclein preformed fibril (PFF) propagation model and the transgenic PLP-α-syn model expressing human wild-type α-synuclein in oligodendrocytes. Pharmacokinetic analyses assessed plasma and brain exposure after oral administration. The efficacy of six-month dapansutrile treatment was examined in both preventive (post-PFF injection) and therapeutic (PLP-α-syn mice) paradigms, using behavioral, histopathological, and molecular readouts. Transcriptomic profiling of striatal and midbrain microglia identified differentially expressed genes (DEGs) associated with treatment and compared them with post-mortem transcriptomic signatures of disease-associated microglia in PD patients. Plasma IL-18 and neurofilament light chain (NfL) levels were evaluated as translational biomarkers.

Chronic oral dapansutrile treatment at clinically relevant doses improved motor performance, reduced α-synuclein inclusions, attenuated gliosis, and mitigated nigral neurodegeneration in both models. Microglial transcriptomic analyses revealed that dapansutrile reversed key transcriptional signatures characteristic of PD-associated reactive microglia. Moreover, plasma IL-18 and NfL levels correlated with neuropathological and functional outcomes, supporting their potential as biomarkers of target engagement and treatment efficacy.

These data identify chronic NLRP3 activation as a shared and targetable mechanism in PD and MSA and highlight dapansutrile as a CNS-penetrant, clinically advanced candidate for disease modification in α-synucleinopathies. The observed transcriptomic reprogramming of microglia and the parallel changes in blood biomarkers provide a strong translational bridge to clinical development.

The online version contains supplementary material available at 10.1186/s12974-026-03716-3.