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  • Synaptic disruption and CREB-regulated transcription are restored by K+ channel blockers in ALS.

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

EMBO molecular medicine (2021-06-15)
Alberto Catanese, Sandeep Rajkumar, Daniel Sommer, Dennis Freisem, Alexander Wirth, Amr Aly, David Massa-López, Andrea Olivieri, Federica Torelli, Valentin Ioannidis, Joanna Lipecka, Ida Chiara Guerrera, Daniel Zytnicki, Albert Ludolph, Edor Kabashi, Medhanie A Mulaw, Francesco Roselli, Tobias M Böckers
摘要

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 ALSC9orf72 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.

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Sigma-Aldrich
抗-寡糖-2 抗体, Chemicon®, from rabbit
Sigma-Aldrich
Anti-Potassium Channel SK2 antibody produced in rabbit, affinity isolated antibody, lyophilized powder