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Abstract:
Parkinson’s disease (PD) etiology is associated with genetic and environmental factors that lead to a loss ofdopaminergic neurons. However, the functional interpretation of PD-associated risk variants and how othermidbrain cells contribute to this neurodegenerative process are poorly understood. Here, we profiled >41,000single-nuclei transcriptomes of postmortem midbrain tissue from 6 idiopathic PD (IPD) patients and 5matched controls. We show that PD-risk variants are associated with glia- and neuron-specific geneexpression patterns. Furthermore, Microglia and astrocytes presented IPD-specific cell proliferation anddysregulation of genes related to unfolded protein response and cytokine signalling. IPD-microglia revealeda specific pro-inflammatory trajectory. Finally, we discovered a neuronal cell cluster exclusively present inIPD midbrains characterized byCADPS2overexpression and a high proportion of cycling cells. Weconclude that elevated CADPS2 expression is specific to dysfunctional dopaminergic neurons, which havelost their dopaminergic identity and unsuccessful attempt to re-enter the cell cycle.
