Spatial multi-omics reveals region-specific molecular signatures in a 6-OHDA model of Parkinson's disease.

Parkinson's disease (PD) is characterized by complex molecular and circuit-level alterations that extend beyond dopaminergic neurodegeneration, yet the spatial integration of metabolic and proteomic changes remains insufficiently explored. Here, we combined time-of-flight secondary ion mass spectrometry-based metabolite imaging with laser cell sorting proteomics to interrogate molecular alterations in the substantia nigra and striatum of the 6-hydroxydopamine toxin model of PD. Our analyses revealed distinct region-specific metabolic and proteomic signatures within primary lesion sites, and additionally uncovered unexpected and widespread off-target changes across neural circuits. These findings demonstrate that even in a toxin-induced model, PD pathology involves extensive reorganization of molecular networks and circuit-level processes, underscoring the complexity and diffuseness of disease mechanisms. By applying a spatially resolved, multilayered approach, this study expands the pathophysiological understanding of PD and provides a foundation for future investigations into the spatial and temporal dynamics of neurodegenerative disease progression.