MALDI Mass Spectrometry Imaging Reveals Early, Tissue-Specific Sphingolipid Dysregulation Across the Brain-Gut-Skin Axis in a GBA1 D409V Parkinson's Disease Mouse Model

Background: Mutations in the GBA1 gene, leading to glucocerebrosidase (GCase) deficiency, are a major genetic risk factor for Parkinson's disease (PD). While systemic sphingolipid alterations are implicated, their spatial distribution in preclinical stages across central and peripheral tissues remains unclear. Methods: We employed MALDI-MSI to map sphingolipid profiles in the brain, gut, and skin of 12-week-old GBA1 D409V knock-in (KI) mice, an early-stage model of GCase deficiency. Relative lipid intensities were quantified within anatomically defined ROIs. Results: In the brain, homozygous KI mice showed significant accumulation of glucosylceramide (GlcCer) species and GM1 ganglioside specifically within the caudate putamen (CPu) compared to heterozygous mice. Along the gastrointestinal tract, GlcCer (d18:1/18:0) levels progressively increased from the duodenum to the colon, with the most profound accumulation observed in the colonic mucosa of homozygous mice. In the skin, the viable epidermis of homozygous mice exhibited significantly elevated levels of GlcCer (18:1/24:0) and a putative sulfated hexosylceramide. Conclusion: Our findings demonstrate that GCase deficiency induces early, spatially restricted, and tissue-specific sphingolipid alterations across the brain-gut-skin axis prior to overt neurodegeneration. This study establishes a spatially-anchored lipidomic framework, highlighting the colonic mucosa and epidermis as potential sites for accessible biomarker discovery in GBA1-associated parkinsonism.