Synaptic disruption and CREB‐regulated transcription are restored by K+ channel blockers in ALS

Abstract

Synopsis

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The lack of an effective treatment for ALS is calling for the development of novel therapeutic strategies. By using hiPSC‐derived motoneurons and focusing on synapse‐related processes, we provide new molecular targets rescuing the degenerative processes and neuronal loss in ALS.

Human C9orf72‐mutant motoneurons are characterized by reduced expression of synaptic gene, progressive loss of CREB activity and synapse loss. Similar alterations are observed also in motoneurons harboring TBK1 pathogenic mutations, and in primary neurons upon overexpression of poly(GA) aggregates. The K+ channel blockers Apamin and XE991 revert the CREB‐dependent loss of synaptic contacts and rescue the degenerative phenotypes of ALS motoneurons.