Brain lipid dysregulation distinguishes Parkinson’s disease and multiple system atrophy

Parkinson’s disease (PD) and multiple system atrophy (MSA) are synucleinopathies with overlapping clinical features but distinct cellular pathology, characterized by neuronal α-synuclein inclusions in PD and oligodendrocyte inclusions in MSA. Although lipid dysregulation is increasingly implicated in synucleinopathies, region-specific lipid differences between PD and MSA remain poorly defined. We therefore performed multi-regional lipidomics analysis of the amygdala, cerebellum, motor cortex, and visual cortex from PD, MSA, and control brains. Anatomical region was the primary driver of lipidomic variance, with disease-related effects superimposed on region-specific lipid clusters. MSA exhibited broader lipid perturbations, characterized by larger fold changes, wider distribution profiles, and greater enrichment of altered lipid classes across multiple brain regions. In contrast, PD showed more modest and regionally restricted lipid alterations. The cerebellum provided the clearest separation between PD and MSA. Direct PD-versus-MSA comparisons revealed distinct disease-specific lipid profiles across all regions, with particularly marked differences in the amygdala and visual cortex. Collectively, these findings indicate that MSA is associated with more extensive lipid dysregulation than PD, likely reflecting widespread oligodendrocyte dysfunction and membrane instability. These results provide new insight into the molecular basis of synucleinopathies and may aid future efforts toward differential diagnosis and therapeutic development.