Cellular prion protein levels modulate nigrostriatal vulnerability to α-synuclein oligomers in Parkinson’s disease
α-Synuclein oligomer (αSynO)-mediated neurodegeneration is a hallmark of Parkinson’s disease (PD) pathogenesis, yet the molecular mechanisms mediating this toxicity remain elusive. In this study, we investigated the cellular prion protein (PrP C ) as a key modulator of αSynO-induced neurodegeneration using an integrative translational approach combining human transcriptomic analysis with in vivo bidirectional genetic modulation in mice. Bioinformatics analysis of postmortem substantia nigra samples revealed that the PRNP gene is significantly upregulated in idiopathic PD patients, with its co-expression network enriched for plasma membrane raft organization and synaptic vesicle dynamics. Single-cell RNA-seq confirmed that PRNP expression is predominantly neuronal and expressed at low levels in microglia. To validate these findings, we performed intrastriatal αSynO injections in PrP C -knockout (PrnpKO), PrP C -overexpressing (Tg20), and wild-type (WT) mice. Immunohistochemical analysis at 30 days post-injection revealed that dopaminergic vulnerability was determined by PrP C expression levels. Tg20 mice exhibited reduced tyrosine hydroxylase immunoreactivity in the caudate-putamen, while PrnpKO mice were protected. Behavioral assessment showed that PrP C levels modulate baseline motor performance, with Tg20-αSynO mice consistently displaying the most severe motor impairment. RT-qPCR analysis of striatal transcripts/mRNA levels revealed genotype-specific neuroinflammatory responses to αSynO. WT mice mounted a selective anti-inflammatory Arginase 1 response, PrnpKO mice partially resolved their basal pro-inflammatory profile, whereas Tg20 mice exhibited pro-inflammatory exacerbation with significant upregulation of Tnfα and Il1β . Together, these findings identify PrP C expression levels as an important modulator of nigrostriatal vulnerability and neuroinflammatory phenotype in response to αSynO, supporting the hypothesis that PrP C contributes to αSynO-mediated pathogenic mechanisms.