GBA1 mutations drive upregulation of LCN2 across multiple in vivo and in vitro models, and LCN2 promotes α-synuclein accumulation, oxidative stress, and dopaminergic neuron loss while genetic deletion or antibody intervention mitigates these effects.

This provides strong preclinical target validation of LCN2 as a druggable downstream mediator linking GBA1-related lysosomal dysfunction to inflammation, ROS and α-syn pathology, offering a clear translational path for antibody/small-molecule therapies or biomarker development in GBA1-associated…

GBA1 is the most frequently mutated gene in patients with sporadic Parkinson's disease (PD), and carriers of GBA1 mutations exhibit an earlier age of PD onset and more severe clinical phenotypes. In an MPTP-induced PD model, we observed that Gba1 F213I point mutation mice displayed a more severe dopaminergic neuron loss in substantia nigra pars compacta (SNpc). Combined analysis of gene expression differences in the brain tissues of Gba1F213I/+ mice, tamoxifen-induced early-stage (7 days) Gba1flox/F213I; UBC-CreERT2 mice, Gba1flox/flox; Nestin-Cre mice, and mice treated with Gcase enzyme inhibitor conduritol-β-epoxid (CBE) revealed significant upregulation of Lcn2, which was further validated by Western blot and immunofluorescence staining in Gba1F213I/+ and tamoxifen-induced Gba1flox/F213I; UBC-CreERT2 mice. Stereotactic injections of AAV9 expressing the GBA1 L444P mutation into the SNpc, as well as GBA1 knockdown or expression of GBA1 mutants in neuro-derived cell lines, also resulted in upregulation of LCN2 expression. Stereotactic injections of recombinant Lcn2 protein promoted α-synuclein accumulation and dopaminergic neuron loss in the SNpc of Gba1F213I/+ mice. In vitro, LCN2 antibodies reduced the intracellular ROS levels induced by GBA1 mutants. Lcn2 knockout alleviated MPTP-induced dopaminergic neuron loss in the SNpc of the Gba1F213I/+ mice and the mice expressing the GBA1 L444P mutant. In conclusion, this study shows that GBA1 mutations increase LCN2 expression, which promotes neuronal damage, and deletion of LCN2 can alleviate the loss of dopaminergic neurons in the GBA1 mutation-associated models.