Single nuclear RNA sequencing shows altered microglial and astrocytic functions in post-mortem Parkinson's disease tissue.

Abstract

Background: Parkinson's disease (PD) is a neurodegenerative disease marked by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and formation of misfolded protein aggregates. A growing body of research has implicated glial cell dysfunction in PD etiology, including the concentration of activated glial cells around protein aggregates in post-mortem tissue. A disruption in the balance of pro- and anti-inflammatory immune response functions of microglia and astrocytes is believed to contribute towards neuronal degeneration as the disease progresses. However, the molecular mechanisms remain unclear. To shed light on the role of microglia and astrocytes in PD, this study analyzes three public single nuclear RNA sequencing datasets of the SNpc from patient and control post-mortem brains to identify altered molecular pathways in PD.

Results: Both astrocytes and microglia show significant upregulation of heat shock binding and misfolded protein response pathways, likely reflecting a response to accumulating protein aggregates. Additionally, both cell types show decreased expression of genes associated with receptor functions; for microglia this included cytokine receptor genes such as IL21R, IL4R, and IFI44L. Genes associated with resting state microglia and non-inflammatory reactive state microglia were downregulated in PD microglia, including P2RY13, RSAD2, CSF2RA, CSF3R, and CX3CR1. Concurrently, astrocytes and microglia both show decreased expression of genes associated with neurotransmitter receptor functions that include glutamate and other ion channel receptors, suggesting a loss of neuron-glia communication in later disease stages.

Conclusions: Taken together, our findings imply that astrocytes and microglia respond to protein misfolding pathology in PD by upregulating chaperone protein folding functions. Additionally, the profile of upregulated functions implies that both cell types are under increased energetic demand. The downregulation of neurotransmitter and channel receptor functions in both cell types indicates that neuron-glia communication and other supportive functions may be lost in favour of autophagic, protein-clearance mechanisms in PD microglia and astrocytes.