Exploring the Role of Glycosphingolipid Metabolism in Disease Pathogenesis Across Lysosomal Storage Disorders, Neurodegeneration, and Cancer

Alterations in glycosphingolipid (GSL) metabolism serve as a critical nexus linking lysosomal storage disorders (LSDs), neurodegeneration, and cancer progression. In LSDs, such as Gaucher disease, GBA1 mutations drive glucosylceramide (GlcCer) accumulation, destabilizing lysosomal enzyme trafficking and hydrolytic capacity. This lysosomal collapse manifests in hepatosplenomegaly, skeletal defects, and neurotoxic ɑ-synuclein aggregation due to impaired autophagic clearance. In Parkinson’s disease (PD) models, GSL imbalances exacerbate lysosomal dysfunction, with ganglioside dysregulation (GM1 reduction, GM3 elevation) promoting ɑ-synuclein oligomerization through failed lysosomal degradation. Mechanistically, lysosomal stress triggers compensatory LAMP1 upregulation and mTOR hyperactivation, which suppress TFEB- mediated lysosomal biogenesis, perpetuating a cycle of autophagic failure. Concurrently, lysosomal dysfunction drives aberrant signaling: retained growth factor receptors (EGFR, PDGF) evade degradation, hyperactivating pro-survival kinases (p-Akt) that fuel epithelial-mesenchymal transition (EMT) in cancer. GSL accumulation reshapes lipid raft microdomains, disturbing the spatial organization of signaling complexes and enabling constitutive activation of oncogenic pathways (P13K/Akt, EGFR) while impairing neurotrophic receptor (TrkB) clustering, bridging membrane biophysical changes to disease progression. These insights position lysosomal dysfunction and lipid raft-driven signaling alterations as central drivers of GSL-mediated pathology, offering unified strategies to combat LSDs, neurodegeneration, and cancer.