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

• DOI: 10.1093/brain/awab446
• Publication Date: 2021-12-13T20:16:42Z
• Authors: Semra Smajić; Cesar A. Prada-Me...; Zied Landoulsi; Jenny Ghelfi; Sylvie Delcambre; Carola Dietrich; Javier Jarazo; Jana Henck; Saranya Balachandran; Sinthuja Pachchek; Christopher M. Mo...; Paul Antony; Bernd Timmermann; Sascha Sauer; Sandro L. Pereira; Jens C. Schwamborn; Patrick May; Anne Grünewald; Malte Spielmann
• Keywords: Membrane Glycoproteins; Dopaminergic Neurons; microglia; Parkinson Disease; single-cell sequencing; : Biochemistry, biophysics & molecular biology [F05] [Life sciences]; neuroinflammation; 3. Good health; Substantia Nigra; Mesencephalon; Parkinson’s disease; Humans; Original Article; Microglia; Technology Platforms; Genes, Cells and Cell-Based Medicine [Topic 1]; : Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant]; midbrain substantia nigra; Genome-Wide Association Study

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