Synaptic disruption and CREB‐regulated transcription are restored by K+ channel blockers in ALS. Issue 7 (14th June 2021) - Catanese, Alberto
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which is still missing effective therapeutic strategies. Although manipulation of neuronal excitability has been tested in murine and human ALS models, it is still under debate whether neuronal activity might represent a valid target for efficient therapies. In this study, we exploited a combination of transcriptomics, proteomics, optogenetics and pharmacological approaches to investigate the activity‐related pathological features of iPSC‐derived C9orf72‐mutant motoneurons (MN). We found that human ALS C9orf72 MN are characterized by accumulation of aberrant aggresomes, reduced expression of synaptic genes, loss of synaptic contacts and a dynamic "malactivation" of the transcription factor CREB. A similar phenotype was also found in TBK1‐mutant MN and upon overexpression of poly(GA) aggregates in primary neurons, indicating a strong convergence of pathological phenotypes on synaptic dysregulation. Notably, these alterations, along with neuronal survival, could be rescued by treating ALS‐related neurons with the K + channel blockers Apamin and XE991, which, respectively, target the SK and the Kv7 channels. Thus, our study shows that restoring the activity‐dependent transcriptional programme and synaptic composition exerts a neuroprotective effect on ALS disease progression. Synopsis: 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. Abstract : 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.