Correlation Engine 2.0
Clear Search sequence regions

Sizes of these terms reflect their relevance to your search.

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.


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. Cx43 hemichannels contribute to astrocyte-mediated toxicity in sporadic and familial ALS. Proceedings of the National Academy of Sciences of the United States of America. 2022 Mar 29;119(13):e2107391119

Expand section icon Mesh Tags

Expand section icon Substances

PMID: 35312356

View Full Text