Connexin 43 is downregulated in advanced Parkinson’s disease in multiple brain regions which correlates with symptoms

Parkinson's disease (PD) is a neurodegenerative condition with the greatest increase in disability globally. Dysfunction of dopaminergic neurons is a well-known PD hallmark; however, changes in astrocytes also accompany PD progression. One aspect of astrocyte biology not yet investigated in PD is their network coupling. To assess this, we focussed on the major astrocytic gap junctional protein connexin 43 (Cx43, GJA1). A dataset of 20 post-mortem late-stage PD brain tissue samples from the cortex and basal ganglia alongside 20 age-matched control sets was collected, accompanied by clinical histories and data on α-synuclein, tau, and amyloid-β pathology. Protein levels and intracellular distribution of Cx43 and other key markers were measured. Computational re-analysis of open-source mRNA sequencing datasets from the striatum and midbrain complemented the original findings. Two novel observations were made: first, profound Cx43 loss in late-stage PD, and second, differential manifestation of this pathology in different brain areas, including those outside of the midbrain substantia nigra-the region that is most commonly used in PD research. Cx43 downregulation in specific regions correlated with non-motor symptoms of PD such as depression and sleep disturbance. Astrocytic tree simplification in the frontal cortex was further observed. In conclusion, astrocytic network decoupling through Cx43 downregulation in PD may contribute to astrocytic dysfunction and PD symptom development.