Single-cell sequencing of the human midbrain reveals glial activation and a neuronal state specific to Parkinson's disease [article]

Semra Smajic, Cesar Augusto Prada-Medina, Zied Landoulsi, Carola Dietrich, Javier Jarazo, Jana Henck, Saranya Balachandran, Sinthuja Pachchek, Christopher M Morris, Paul Antony, Bernd Timmermann, Sascha Sauer (+4 others)
2020 medRxiv   pre-print
Parkinson'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-
more » ... 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.
doi:10.1101/2020.09.28.20202812 fatcat:i6zhm23b6vaijnw6ujmya7ptqm