Cx43 hemichannels contribute to astrocyte-mediated toxicity in sporadic and familial ALS

Autor: Akshata A. Almad, Arens Taga, Jessica Joseph, Sarah K. Gross, Connor Welsh, Aneesh Patankar, Jean-Philippe Richard, Khalil Rust, Aayush Pokharel, Caroline Plott, Mauricio Lillo, Raha Dastgheyb, Kevin Eggan, Norman Haughey, Jorge E. Contreras, Nicholas J. Maragakis
Rok vydání: 2022
Předmět:
Zdroj: Proceedings of the National Academy of Sciences of the United States of America, vol 119, iss 13
ISSN: 1091-6490
0027-8424
Popis: Connexin 43 (Cx43) gap junctions and hemichannels mediate astrocyte intercellular communication in the central nervous system under normal conditions and contribute to astrocyte-mediated neurotoxicity in amyotrophic lateral sclerosis (ALS). Here, we show that astrocyte-specific knockout of Cx43 in a mouse model of ALS slows disease progression both spatially and temporally, provides motor neuron (MN) protection, and improves survival. In addition, Cx43 expression is up-regulated in human postmortem tissue and cerebrospinal fluid from ALS patients. Using human induced pluripotent stem cell–derived astrocytes (hiPSC-A) from both familial and sporadic ALS, we establish that Cx43 is up-regulated and that Cx43-hemichannels are enriched at the astrocyte membrane. We also demonstrate that the pharmacological blockade of Cx43-hemichannels in ALS astrocytes using GAP 19, a mimetic peptide blocker, and tonabersat, a clinically tested small molecule, provides neuroprotection of hiPSC-MN and reduces ALS astrocyte-mediated neuronal hyperexcitability. Extending the in vitro application of tonabersat with chronic administration to SOD1G93A mice results in MN protection with a reduction in reactive astrocytosis and microgliosis. Taking these data together, our studies identify Cx43 hemichannels as conduits of astrocyte-mediated disease progression and a pharmacological target for disease-modifying ALS therapies.
Databáze: OpenAIRE
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