Roles of astrocytic Connexin 43 gap junctional deficit in alpha-synucleinopathy and inflammation relevant to Parkinson's

Parkinson's disease (PD) is a neurological condition with the fastest rise in prevalence globally; it affects over 10 million people and is currently incurable. Originally considered purely a disorder of the dopaminergic nigrostriatal pathway, PD is increasingly recognized as a complex pathology affecting different cell types and multiple brain regions beyond substantia nigra of midbrain. These findings call for new conceptual approaches to translational research in PD which would aim to restore functions of multiple cell types. We previously demonstrated a decrease in astrocytic connexin43 (Cx43) protein in human late-stage idiopathic PD, but its functional consequences remain unknown. In the present work we hypothesized that the key etiologies relevant to human idiopathic PD include inflammation and α-synuclein aggregation, which were applied to a number of model systems ranging from rat and human cultured astrocytes, to co-cultures and rat models of PD. We report that these challenges structurally and functionally disrupt astrocytic networks comprised of Cx43-containing gap junctions (GJs) in astrocytes from multiple brain regions and across species (rat, human), and that Cx43 is downregulated in α-synuclein pre-formed fibril-induced rat PD models. Causal rather than correlational roles of Cx43 dysfunction in PD pathology are suggested as experimental downregulation of Cx43 with shRNA dysregulates calcium signaling and exacerbates α-synuclein aggregation, while pharmacological preservation of GJs (and possible hemichannel closure) using a Cx43-modulating compound danegaptide (GAP-134, ZP1609) reduces aspects of pathology induced by inflammation and α-synuclein in vitro and in vivo. Cx43 may therefore represent a new therapeutic target for disease modification in PD.