Objective: To determine whether the GBA1 L444P mutation increases susceptibility to neuroinflammation and alters immune responses during CNS inflammatory challenge.
Background: Mutations in GBA1, which encodes the lysosomal enzyme glucocerebrosidase, represent the most common genetic risk factor for Parkinson’s disease. Lysosomal dysfunction has been increasingly implicated in immune dysregulation and neuroinflammatory processes. However, whether GBA1 mutations increase vulnerability to neuroinflammatory insults in the CNS remains unclear.
Method: Two-month-old GBA1 L444P knock-in mice and wild-type littermates were divided into four groups: wild-type control, wild-type + experimental autoimmune encephalomyelitis (EAE), GBA1 control, and GBA1 + EAE (n = 5 per group). EAE was induced as a controlled neuroinflammatory challenge to evaluate susceptibility to immune-mediated CNS inflammation. Clinical scores were recorded and motor coordination was assessed using the rotarod test. Demyelination and astrocyte activation were evaluated by histological and immunofluorescence analyses. Peripheral immune cell populations were analyzed by flow cytometry.
Results: GBA1 L444P mice developed earlier disease onset and greater clinical severity following EAE induction compared with wild-type controls. Histological analysis revealed more pronounced corpus callosum demyelination and increased astrocyte activation in the hippocampus of GBA1 mutant mice. Flow cytometry demonstrated increased frequencies of CD8⁺ IFN-γ⁺ T cells, a higher proportion of macrophages, and reduced IL-10⁺CD19⁺ regulatory B cells in the peripheral immune compartment, indicating a shift toward a pro-inflammatory immune response.
Conclusion: These findings indicate that the GBA1 L444P mutation increases susceptibility to neuroinflammation and promotes a pro-inflammatory immune response, supporting a role for GBA1 in modulating neuroimmune mechanisms potentially relevant to Parkinson’s disease pathogenesis.
To cite this abstract in AMA style:
R. Wang, D. Cossu, Y. Tomizawa, T. Hatano, N. Hattori. GBA1 L444P mutation increases susceptibility to neuroinflammation and promotes pro-inflammatory immune responses [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/gba1-l444p-mutation-increases-susceptibility-to-neuroinflammation-and-promotes-pro-inflammatory-immune-responses/. Accessed October 1, 2026.« Back to 2026 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/gba1-l444p-mutation-increases-susceptibility-to-neuroinflammation-and-promotes-pro-inflammatory-immune-responses/