PT  - JOURNAL ARTICLE
AU  - Akshata A. Almad
AU  - Arens Taga
AU  - Jessica Joseph
AU  - Connor Welsh
AU  - Aneesh Patankar
AU  - Sarah K. Gross
AU  - Jean-Philippe Richard
AU  - Aayush Pokharel
AU  - Mauricio Lillo
AU  - Raha Dastgheyb
AU  - Kevin Eggan
AU  - Norman Haughey
AU  - Jorge E. Contreras
AU  - Nicholas J. Maragakis
TI  - Connexin 43 hemichannels mediate spatial and temporal disease spread in ALS
AID  - 10.1101/2020.03.14.990747
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.03.14.990747
4099  - http://biorxiv.org/content/early/2020/03/15/2020.03.14.990747.short
4100  - http://biorxiv.org/content/early/2020/03/15/2020.03.14.990747.full
AB  - Connexin 43 (Cx43) gap junctions and hemichannels mediate astrocyte intercellular communication in the central nervous system under normal conditions and may 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 human ALS tissues and biofluids, we observe that higher levels of Cx43 correlate with accelerated disease progression. Using human iPSC-derived astrocytes (hiPSC-A) from both familial and sporadic ALS, we show that Cx43 is upregulated and that Cx43-hemichannels are enriched at the astrocyte membrane. We then demonstrate that the pharmacological blockade of Cx43-hemichannels in ALS astrocytes, during a specific temporal window, provides neuroprotection of hiPSC-MN and reduces ALS astrocyte-mediated neuronal hyperexcitability. Our data identify Cx43 hemichannels as novel conduits of astrocyte-mediated disease progression and a pharmacological target for disease-modifying ALS therapies.