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

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

  • Exp Neurol. 2026 Jun 26:115897. doi: 10.1016/j.expneurol.2026.115897.
Nataly Hastings 1,  Saifur Rahman 2,  Wei-Li Kuan 3,  Maha Alfaidi 4,  Sarah Fox 4,  Nadia A Erkamp 5,  Ewa Andrzejewska 5,  Michael Whitehead 4,  Aleksandr Zakirov 4,  Richard D Unwin 6,  Koby Baranes 2,  Ronny Schmidt 7,  Anna Oliinyk 8,  Donya Aref 8,  Jonathan Brotchie 8,  Tuomas P J Knowles 8,  George G Malliaras 9,  Mark R N Kotter 2
Affiliations

Affiliations

  • 1 Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, United Kingdom; Electrical Engineering Division, Department of Engineering, University of Cambridge, Cambridge CB3 0FA, United Kingdom; Cellestial Health Ltd, Cambridge CB4 0WS, United Kingdom. Electronic address: [email protected].
  • 2 Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, United Kingdom.
  • 3 Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, United Kingdom; ALBORADA Drug Discovery Institute, University of Cambridge, Cambridge CB2 0AH, United Kingdom.
  • 4 Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
  • 5 Yusuf Hamied Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
  • 6 Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9NT, United Kingdom.
  • 7 Sciomics GmbH, Neckargemünd 69151, Germany.
  • 8 Atuka Inc, Toronto, Ontario M5G 0A3, Canada.
  • 9 Electrical Engineering Division, Department of Engineering, University of Cambridge, Cambridge CB3 0FA, United Kingdom.
PMID: 42362037 DOI: 10.1016/j.expneurol.2026.115897
Abstract

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, 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 compounds 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.

Keywords

Alpha-Synuclein; Astrocyte; Connexin43; Gap Junction; Inflammation; Parkinson’s.

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