Astrocytic networks as a novel therapeutic target in Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a neurodegenerative condition with the highest rise in disability and is currently incurable. Dopamine replacement therapies reduce motor symptoms temporarily, but do not address non-motor symptoms (NMS) of PD, and often cause serious side effects; with up to 10 million people with PD worldwide and predicted economic burden of over £79 billion in the US alone by 2037, the unmet clinical need is large. Deeper understanding of PD pathology is required to create new transformative therapies. One cell type that received increasing attention in PD recently is astrocytes. Astrocytes express multiple familial PD-associated genes as much, or more than neurones, and develop alpha-synuclein (a-syn) immunoreactivity which correlates with dopaminergic loss. Their causal involvement in PD symptom development was demonstrated in vitro and in vivo, where healthy astrocytes could rescue functions of neurones carrying PD mutations and reduce motor symptoms in rodent models, and diseased astrocytes could induce PD-resembling dysfunction in heathy neurones or animal models. A key aspect of astrocyte biology is their ability to form large networks transmitting calcium signals. Abnormal calcium signalling is also a hallmark of PD. We hypothesised that astrocyte networks are dysregulated in PD, and normalising calcium transmission in astrocyte networks could reduce a-syn aggregation and inflammation. Our first target is connexin43 (Cx43) which connects astrocytes via gap junctions (GJs) and promotes calcium transmission, and dysregulation of which is linked to inflammasome activation through hemichannel (HC) opening.