A neuropeptide receptor–enriched transcriptional state characterizes resilient dopaminergic neurons in Parkinson's disease

Dopaminergic neurons (DANs) exhibit subtype-specific vulnerability in Parkinson's disease (PD), but the molecular basis of selective resilience remains poorly understood. Here, we investigated the role of neuropeptide receptor (NPR) signaling in DAN survival using single-nucleus RNA sequencing of 8065 DANs from postmortem substantia nigra of individuals with PD and matched controls. Despite pronounced neuronal loss in PD, surviving DANs showed a higher NPR transcript burden and increased NPR gene co-expression per cell. Using a 25-gene NPR score, we stratified DANs into high-, mid-, and low-NPR tiers and identified distinct molecular signatures. High-NPR DANs exhibited increased expression of the resilience marker CALB1 and an inverse correlation with PD genetic-risk signals. Low-NPR DANs preferentially expressed vulnerability markers (SOX6, ALDH1A1, AGTR1) and displayed a positive association with PD genetic risk. Notably, Mitochondrial Complex I subunits (NDUFS2, NDUFB10) were relatively enriched in low-NPR DANs at baseline and were further reduced in PD specifically within this tier. Among dopaminergic subtypes, the PD-susceptible SOX6_AGTR1 neurons displayed minimal NPR activity, while resilient CALB1⁺ subtypes showed elevated NPR signaling. Moreover, SOX6_AGTR1 neurons preferentially expressed the transcription factors PGR and CLOCK, but the expression of both factors was significantly reduced in PD within this subtype, with no significant change in CALB1⁺ subtypes. Integrating these findings with genome-wide association study (GWAS) enrichment and external datasets, we identified PRLR and CRHR1 as key mediators of dopaminergic resilience, highlighting their potential as targets for neuroprotective therapy. Together, our data implicate NPR signaling as a molecular correlate of dopaminergic resilience in PD and highlight specific receptor pathways for therapeutic development.