Connexin 43 hemichannels and pannexin‐1 channels contribute to the α‐synuclein‐induced dysfunction and death of astrocytes

• Published in: Glia 2019-08, Vol.67 (8), p.1598-1619
• Main Authors: Díaz, Esteban F., Labra, Valeria C., Alvear, Tanhia F., Mellado, Luis A., Inostroza, Carla A., Oyarzún, Juan E., Salgado, Nicole, Quintanilla, Rodrigo A., Orellana, Juan A.
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - genetics; Animals; Astrocytes; Astrocytes - pathology; Calcium (intracellular); Calcium Channels - genetics; Calcium Channels - metabolism; Calcium ions; Calcium oxide; Calcium signalling; Cell Communication - genetics; Cell Death - genetics; Cells, Cultured; Channels; connexin; Connexin 43; Connexin 43 - genetics; Connexins - genetics; Cortex; Crosstalk; Cyclooxygenase-2; Cytokines; Cytokines - metabolism; Cytosol; Dementia disorders; glia; Glial cells; Glutamatergic transmission; Inclusion bodies; Inclusions; Intracellular signalling; Kinases; Lewy bodies; MAP kinase; Mice; Mitochondria; Mitochondria - genetics; Mitochondria - ultrastructure; Morphology; Movement disorders; Nerve Tissue Proteins - genetics; Neurodegenerative diseases; neuroinflammation; Neuronal-glial interactions; Neurotransmitter Agents - metabolism; Nitric oxide; Nitric Oxide - biosynthesis; Nitric-oxide synthase; pannexin; Parkinson's disease; Pathogenesis; RNA, Small Interfering - genetics; Synuclein; α‐synucleinopathies
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.23631

Diverse studies have suggested that cytoplasmic inclusions of misfolded α‐synuclein in neuronal and glial cells are main pathological features of different α‐synucleinopathies, including Parkinson's disease and dementia with Lewy bodies. Up to now, most studies have focused on the effects of α‐synuclein on neurons, whereas the possible alterations of astrocyte functions and neuron–glia crosstalk have received minor attention. Recent evidence indicates that cellular signaling mediated by hemichannels and pannexons is critical for astroglial function and dysfunction. These channels constitute a diffusional route of communication between the cytosol and the extracellular space and during pathological scenarios they may lead to homeostatic disturbances linked to the pathogenesis and progression of different diseases. Here, we found that α‐synuclein enhances the opening of connexin 43 (Cx43) hemichannels and pannexin‐1 (Panx1) channels in mouse cortical astrocytes. This response was linked to the activation of cytokines, the p38 MAP kinase, the inducible nitric oxide synthase, cyclooxygenase 2, intracellular free Ca2+ concentration ([Ca2+]i), and purinergic and glutamatergic signaling. Relevantly, the α‐synuclein‐induced opening of hemichannels and pannexons resulted in alterations in [Ca2+]i dynamics, nitric oxide (NO) production, gliotransmitter release, mitochondrial morphology, and astrocyte survival. We propose that α‐synuclein‐mediated opening of astroglial Cx43 hemichannels and Panx1 channels might constitute a novel mechanism involved in the pathogenesis and progression of α‐synucleinopathies. Main Points α‐Synuclein activates Cx43 hemichannels and Panx1 channels in astrocytes. Opening of Cx43 hemichannels and Panx1 channels disturbs [Ca2+]i dynamics, NO production, gliotransmitter release, mitochondrial morphology, and survival of astrocytes.