Spatial lipidomics identifies α-synuclein-induced lipid changes in an AAV-induced Parkinsonian mouse model

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. • MALDI-MSI revealed a spatially resolved lipidomic landscape in an AAV-α-synuclein-induced Parkinsonian mouse model. • Sphingolipids, including ganglioside GM1s, sphingomyelins, and sulfatides, changed differently in the striatum and substantia nigra. • Polyunsaturated species of glycerophospholipids were decreased, while saturated and monounsaturated species were increased, mainly in the substantia nigra. • Oxidized phosphatidylcholines (PCs) were elevated in the substantia nigra. • Ether phosphatidylethanolamines (PEs) were reduced in the substantia nigra but increased in the striatum.