Connexin 43 in astrocytes contributes to motor neuron toxicity in amyotrophic lateral sclerosis

Akshata A. Almad, Arpitha Doreswamy, Sarah K. Gross, Jean Philippe Richard, Yuqing Huo, Norman Haughey, Nicholas J. Maragakis

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons in the CNS. Astrocytes play a critical role in disease progression of ALS. Astrocytes are interconnected through a family of gap junction proteins known as connexins (Cx). Cx43 is a major astrocyte connexin conducting crucial homeostatic functions in the CNS. Under pathological conditions, connexin expression and functions are altered. Here we report that an abnormal increase in Cx43 expression serves as one of the mechanisms for astrocyte-mediated toxicity in ALS. We observed a progressive increase in Cx43 expression in the SOD1G93A mouse model of ALS during the disease course. Notably, this increase in Cx43 was also detected in the motor cortex and spinal cord of ALS patients. Astrocytes isolated from SOD1G93A mice as well as human induced pluripotent stem cell (iPSC)-derived astrocytes showed an increase in Cx43 protein, which was found to be an endogenous phenomenon independent of neuronal co-culture. Increased Cx43 expression led to important functional consequences when tested in SOD1G93A astrocytes when compared to control astrocytes over-expressing wild-type SOD1 (SOD1WT). We observed SOD1G93A astrocytes exhibited enhanced gap junction coupling, increased hemichannel-mediated activity, and elevated intracellular calcium levels. Finally, we tested the impact of increased expression of Cx43 on MN survival and observed that use of both a pan Cx43 blocker and Cx43 hemichannel blocker conferred neuroprotection to MNs cultured with SOD1G93A astrocytes. These novel findings show a previously unrecognized role of Cx43 in ALS-related motor neuron loss.

Original languageEnglish (US)
Pages (from-to)1154-1169
Number of pages16
Issue number7
StatePublished - Jul 1 2016


  • ALS
  • Astrocyte
  • Connexin
  • IPSC
  • Motor neuron

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience


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