Spatial transcriptomics reveals the molecular signatures of prodromal and advanced α-synucleinopathy

A pathological role of α-synuclein (aSyn) aggregation in the etiology of Parkinson disease (PD) is well established. Here, we applied spatial transcriptomics (ST) on brain sections derived from a rodent mouse model of α-synucleinopathy (transgenic M83^+/+ line). Our ST data revealed that induction of aSyn pathology in the brainstem of rodents triggered upregulation of pathways controlling energy metabolism. At a later stage, characterized by movement disability, the ST data indicated a drastic downregulation of mitochondrial metabolic pathways along with perturbed expression of mRNA translation machinery. Furthermore, analyses of microarrays datasets derived from 4 independent cohorts of PD patients led to the identification of aberrant osteopontin (SPP1) signaling and increased expression of CREB-binding protein as consistent markers associated with the progression of aSyn pathology in the rodent model and in PD brains. We anticipate that our findings hold promise for biomarker discovery and/or mechanism-based therapies in PD and related neurodegenerative disorders.