PrPC expression levels determine nigrostriatal degeneration and inflammatory responses to α-synuclein oligomers

Parkinson's disease (PD) involves α-synuclein oligomer (αSynO) toxicity, yet the receptors mediating this remain elusive. This study investigated Cellular Prion Protein (PrP^c) as a mediator of αSynO-induced neurodegeneration. All procedures adhered to the guidelines set by the Animal Use Ethics Committee (CEUA) of the Health Sciences Center (CCS) of UFRJ, approved by protocol number A6/19-001-16. Human transcriptomic analysis showed PRNP upregulation in idiopathic PD, correlating with regional vulnerability, with networks linked to membrane rafts and synaptic vesicles. Single-cell RNA-seq showed PRNP is predominantly neuronal, with low microglial expression, suggesting a neuron-autonomous mechanism. Stereotaxic intrastriatal αSynO was injected into wild-type (WT), PrP^c-knockout (PrnpKO), and PrPC-overexpressing (Tg20) mice. At 30 days, PrP^c expression altered baseline motor behavior (rotarod and pole test). After αSynO injection, Tg20 mice showed the worst functional decline and greatest Tyrosine Hydroxylase loss in the ipsilateral caudate-putamen, while PrnpKO was protected. RT-qPCR showed selective cytokine exacerbation (TNF-α, IL-1β, IL-6) only in Tg20-αSO, whereas WT and PrnpKO showed reduced homeostatic markers (Arg-1, MMP-9). Given microglia's role as primary cytokine-secreting cells in PD, Iba1⁺ morphology was quantified in caudate-putamen. Tg20 microglia showed the most reactive baseline morphology (largest perimeter, area, branching, junctions, arborization, intersections). αSynO increased these parameters across all groups, but Tg20-αSynO remained the most reactive, mirroring its selective cytokine upregulation. Given low microglial PRNP expression, findings suggest PrP^c-driven neuronal stress secondarily recruits a deleterious microglial response. Overall, PrP^c levels determines nigrostriatal vulnerability to αSynO, positioning the PrP^c-αSynO interaction as a neuron-autonomous therapeutic target with downstream effects on microglial activation.