Using dual-polarity MALDI-MSI in an AAV-α-synuclein mouse model, the study maps region-specific lipid changes in the nigrostriatal pathway—altered gangliosides, sphingomyelins and sulfatides in substantia nigra/striatum, a shift from PUFA- to saturated/monounsaturated-containing…

By directly linking α-synuclein overexpression to spatially resolved alterations in sphingolipid and phospholipid metabolism (including lipid oxidation and ganglioside/sulfatide changes), the work highlights actionable lipid pathways and potential biomarkers that could be targeted or monitored in…

Parkinson's disease (PD) is characterized by Lewy body pathology, mainly consisting of accumulation of aggregated α-synuclein and lipid contents. Lipid dyshomeostasis has frequently been observed in PD, and compelling evidences indicate that lipids play critical roles in modulating α-synuclein toxicity. However, how α-synuclein regulates brain lipid composition remains poorly understood. Here, we used dual polarity matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to spatially profile brain lipids in a unilateral adeno-associated virus (AAV)-α-synuclein mouse model of Parkinsonism. We identified region-specific alterations in sphingolipids and glycerophospholipids in the substantia nigra and striatum of these mice. In sphingolipids, α-synuclein overexpression altered certain monosialotetrahexosylgangliosides (GM1s), sphingomyelins (SMs), and sulfated hexosyl ceramides (SHexCers; a.k.a. sulfatides). Glycerophospholipid changes followed a desaturation pattern: polyunsaturated fatty acid (PUFA)-containing species were decreased, while saturated and mono-unsaturated species were increased. Additionally, oxidized phosphatidylcholine (PC) lipids, such as SAzPC (1-stearoyl-2-azelaoyl-sn-PC) and PAzPC(1-palmitoyl-2-azelaoyl-sn-PC), were elevated in the substantia nigra, and ether phosphatidylethanolamines (PEs) were reduced in the substantia nigra but increased in the striatum. Our study provides a comprehensive, spatially resolved lipidomic landscape of α-synuclein-induced pathology in the nigrostriatal pathway, offering new insights into lipid dysregulation in experimental PD and a framework for future therapeutic exploration.