Spatial multi-omics reveals disease-associated oligodendrocytes and metabolic dysregulation in male Parkinson’s disease mouse models

Parkinson’s disease involves progressive α-synuclein pathology, but how this reshapes the brain’s spatial immunometabolic landscape, and how oligodendrocytes participate, remain incompletely defined. Here we combine single-nucleus RNA sequencing, spatial transcriptomics and spatial metabolomics in male A53T α-synuclein transgenic mice across disease stages, together with male mice carrying adeno-associated virus-mediated α-synuclein overexpression, human midbrain and cerebrospinal fluid samples. We describe a disease-associated oligodendrocyte lineage marked by elevated Il33 and Kirrel3 that expands with pathology in both mouse models. Interleukin 33 is upregulated in oligodendrocytes and its receptor ST2 in microglia, and bidirectional manipulation of oligodendrocyte Il33 alters microglial ST2 activation, insoluble α-synuclein burden and motor performance. In the substantia nigra and ventral tegmental area, transcriptomic and metabolomic changes converge on lipid- and glutamate-related pathways. Both proteins are also elevated in human Parkinson’s disease midbrain and cerebrospinal fluid. These data implicate oligodendrocyte interleukin 33–ST2 signalling and provide a spatially resolved resource. Spatial multi-omics of Parkinson’s disease mouse models identifies a disease-associated oligodendrocyte state in which IL-33 signalling to microglial ST2 shapes alpha-synuclein clearance, alongside regional lipid and glutamate metabolic disruption.