Objective: This investigation centers on the role of inflammation in GBA-associated Parkinson’s disease (PD), a neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons, a-synuclein (a-syn) aggregation, and neuroinflammation.
Background: Mutations in the GBA gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the most prevalent genetic risk factors associated with PD. These mutations compromise GCase function, leading to lysosomal dysfunction, glucosylceramide (GlcCer) accumulation, and increased a-syn aggregation, all of which contribute to chronic neuroinflammation.
Microglia, the resident immune cells of the central nervous system, play a critical role in mediating neuroinflammatory processes in PD. Notably, microglial activation is observed both in individuals carrying GBA mutations without PD and in early-stage PD patients, potentially acting as a trigger for the disease and representing a valuable prognostic marker.
A key driver of this inflammatory response is the NF-κB signaling pathway, which has become a focal point in the study of PD inflammation. Its activation can be triggered by damage-associated molecular patterns (DAMPs), such as cell debris, aggregated proteins, or sphingolipids that accumulate in GBA mutated cells. This leads to the release of pro-inflammatory cytokines and an increase in reactive oxygen species (ROS). As a result, microglia adopt a pro-inflammatory phenotype, driving chronic inflammation that results in neuronal damage and neurodegeneration, thereby accelerating disease progression.
Method: To investigate the underlying mechanisms, we employed a Conduritol B epoxide (CBE) treated model to mimic GBA mutations in macrophages.
Results: Our findings demonstrated increased activation of the NF-κB pathway, elevated markers of oxidative stress, and lysosomal dysfunction in CBE treated macrophages.
Conclusion: These results support a model in which GBA mutations contribute to the pathogenesis of PD by promoting a pro-inflammatory state and disrupting cellular homeostasis. Targeting these pathways may offer promising therapeutic strategies for GBA-associated PD.
To cite this abstract in AMA style:
V. Lentini, G. Uras, S. Lucas, D. Moreno-Martinez, A. Manca, F. Fierli, S. Koletsi, A. Pantaleo, D. Hughes. Modeling Inflammation in GBA-Associated Parkinson’s Disease: Insights into Disease Mechanisms [abstract]. Mov Disord. 2025; 40 (suppl 1). https://www.mdsabstracts.org/abstract/modeling-inflammation-in-gba-associated-parkinsons-disease-insights-into-disease-mechanisms/. Accessed October 5, 2025.« Back to 2025 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/modeling-inflammation-in-gba-associated-parkinsons-disease-insights-into-disease-mechanisms/