title: Connexin 43 in astrocytes contributes to motor neuron toxicity in amyotrophic lateral sclerosis.
abstract: 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 SOD1(G93A) 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 SOD1(G93A) 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 SOD1(G93A) astrocytes when compared to control astrocytes over-expressing wild-type SOD1 (SOD1(WT) ). We observed SOD1(G93A) 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 SOD1(G93A) astrocytes. These novel findings show a previously unrecognized role of Cx43 in ALS-related motor neuron loss. GLIA 2016;64:1154-1169.
authors.affiliation: Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, Maryland.
authors.forename: Akshata A
authors.initials: AA
authors.lastname: Almad
authors.affiliation: Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, Maryland.
authors.forename: Arpitha
authors.initials: A
authors.lastname: Doreswamy
authors.affiliation: Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, Maryland.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Gross
authors.affiliation: Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, Maryland.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Richard
authors.affiliation: Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, Maryland.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Huo
authors.affiliation: Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, Maryland.
authors.forename: Norman
authors.initials: N
authors.lastname: Haughey
authors.affiliation: Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, Maryland.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Maragakis
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology*; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000502:physiology; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D013116:Spinal Cord / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D018031:Connexin 43; C514423:Gap 26 peptide; D005904:Glial Fibrillary Acidic Protein; D053583:Interleukin-1beta; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate
keywords: ALS; astrocyte; connexin; iPSC; motor neuron