Antony P

Balachandran S

Delcambre S

Dietrich C

Ghelfi J

Grunewald A

Henck J

Jarazo J

Landoulsi Z

May P

Morris CM

Pachchek S

Pereira SL

Prada-Medina CA

Sauer S

Schwamborn JC

Smajic S

Spielmann M

Timmermann B

\ua9 The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.Idiopathic Parkinson\u27s disease is characterized by a progressive loss of dopaminergic neurons, but the exact disease aetiology remains largely unknown. To date, Parkinson\u27s disease research has mainly focused on nigral dopaminergic neurons, although recent studies suggest disease-related changes also in non-neuronal cells and in midbrain regions beyond the substantia nigra. While there is some evidence for glial involvement in Parkinson\u27s disease, the molecular mechanisms remain poorly understood. The aim of this study was to characterize the contribution of all cell types of the midbrain to Parkinson\u27s disease pathology by single-nuclei RNA sequencing and to assess the cell type-specific risk for Parkinson\u27s disease using the latest genome-wide association study. We profiled &gt;41 000 single-nuclei transcriptomes of post-mortem midbrain from six idiopathic Parkinson\u27s disease patients and five age-/sex-matched controls. To validate our findings in a spatial context, we utilized immunolabelling of the same tissues. Moreover, we analysed Parkinson\u27s disease-associated risk enrichment in genes with cell type-specific expression patterns. We discovered a neuronal cell cluster characterized by CADPS2 overexpression and low TH levels, which was exclusively present in idiopathic Parkinson\u27s disease midbrains. Validation analyses in laser-microdissected neurons suggest that this cluster represents dysfunctional dopaminergic neurons. With regard to glial cells, we observed an increase in nigral microglia in Parkinson\u27s disease patients. Moreover, nigral idiopathic Parkinson\u27s disease microglia were more amoeboid, indicating an activated state. We also discovered a reduction in idiopathic Parkinson\u27s disease oligodendrocyte numbers with the remaining cells being characterized by a stress-induced upregulation of S100B. Parkinson\u27s disease risk variants were associated with glia- and neuron-specific gene expression patterns in idiopathic Parkinson\u27s disease cases. Furthermore, astrocytes and microglia presented idiopathic Parkinson\u27s disease-specific cell proliferation and dysregulation of genes related to unfolded protein response and cytokine signalling. While reactive patient astrocytes showed CD44 overexpression, idiopathic Parkinson\u27s disease microglia revealed a pro-inflammatory trajectory characterized by elevated levels of IL1B, GPNMB and HSP90AA1. Taken together, we generated the first single-nuclei RNA sequencing dataset from the idiopathic Parkinson\u27s disease midbrain, which highlights a disease-specific neuronal cell cluster as well as \u27pan-glial\u27 activation as a central mechanism in the pathology of the movement disorder. This finding warrants further research into inflammatory signalling and immunomodulatory treatments in Parkinson\u27s disease

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Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state

Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state

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