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VULNERABILITIES OF MIDBRAIN DOPAMINERGIC NEURONS TO PARKINSON'S DISEASE REVEALED BY SINGLE-CELL GENOMICS
Abstract
Aims
The loss of some dopamine (DA) neurons within the substantia nigra pars compacta (SNpc) is a defining pathological hallmark of Parkinson’s Disease (PD). Yet, the molecular features associated with DA neuron vulnerability have not yet been fully identified.
Methods
We developed an antibody-based enrichment method, in combination with single-nucleus RNA-sequencing (snRNA-seq), to transcriptionally profile human midbrain DA neurons. We used Slide-seq (Stickels et al., 2021) and in situ hybridization (ISH) to localize these populations within the SNpc. Finally, we applied MAGMA and stratified LD score to nominate which cell types harbor the strongest enrichment of expression of common variants of PD.
Results
We performed snRNA-seq on 387,483 nuclei from 10 individuals with either PD or Lewy body disease (LBD) and 8 age-matched controls, identifying 68 transcriptionally-defined populations. We obtained 22,048 DA neuron profiles, a 180-fold enrichment over previous studies, and identified 10 distinct DA subtypes. With Slide-seq, we localized these 10 populations to the dorsal and ventral tier, and confirmed the localization of a representative set with in situ hybridization in the human midbrain. A single subtype, marked by the expression of the gene AGTR1, was highly susceptible to degeneration and showed the strongest upregulation of TP53 and NR2F2 and their targets, nominating altered pathways associated with degeneration in vivo. This same vulnerable population was uniquely enriched for the heritable risk associated with sporadic PD.
Conclusions
These results highlight the importance of cell-intrinsic pathways in determining the differential vulnerability of DA neurons to degeneration in PD.