Author:
Smajić S.,Prada-Medina C. A.,Landoulsi Z.,Dietrich C.,Jarazo J.,Henck J.,Balachandran S.,Pachchek S.,Morris C. M.,Antony P.,Timmermann B.,Sauer S.,Schwamborn J. C.,May P.,Grünewald A.,Spielmann M.
Abstract
AbstractParkinson’s disease (PD) etiology is associated with genetic and environmental factors that lead to a loss of dopaminergic neurons. However, the functional interpretation of PD-associated risk variants and how other midbrain cells contribute to this neurodegenerative process are poorly understood. Here, we profiled >41,000 single-nuclei transcriptomes of postmortem midbrain tissue from 6 idiopathic PD (IPD) patients and 5 matched controls. We show that PD-risk variants are associated with glia- and neuron-specific gene expression patterns. Furthermore, Microglia and astrocytes presented IPD-specific cell proliferation and dysregulation of genes related to unfolded protein response and cytokine signalling. IPD-microglia revealed a specific pro-inflammatory trajectory. Finally, we discovered a neuronal cell cluster exclusively present in IPD midbrains characterized by CADPS2 overexpression and a high proportion of cycling cells. We conclude that elevated CADPS2 expression is specific to dysfunctional dopaminergic neurons, which have lost their dopaminergic identity and unsuccessful attempt to re-enter the cell cycle.
Publisher
Cold Spring Harbor Laboratory
Cited by
16 articles.
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