Disrupted sphingolipid metabolism drives lysosomal and mitochondrial failure in Parkinson's disease

In human plasma samples and postmortem brain tissue, researchers investigated lysosomal lipid dysregulation in Parkinson’s disease using extracellular vesicle lipidomics. They identified a bidirectional disruption of the ceramide-sphingomyelin axis driven by asymmetric upregulation of the enzymes SMPD1 and SGMS1. Fluorescent lipid tracking showed that SMPD1 disruption severely impairs lysosomal sphingomyelin turnover. This shift triggers a salvage pathway collapse, restricted by SPHK1 and SGPL1 downregulation, which precipitates oxidative membrane damage and PINK1/Parkin-dependent mitophagy failure. The researchers confirmed this pathway dysfunction across cell cultures, mouse models, and human postmortem brains. Furthermore, altered SMPD1 and SGMS1 expression stratified clinical disease phenotypes, specifically identifying patients with the aggressive postural instability and gait difficulty subtype.