Home > Publications Database > Synaptic disruption and CREB-regulated transcription are restored by K+ channel blockers in ALS. > print

001     155693
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024 7 _ |a 10.15252/emmm.202013131
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024 7 _ |a 1715-4684
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037 _ _ |a DZNE-2021-00861
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Catanese, Alberto
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245 _ _ |a Synaptic disruption and CREB-regulated transcription are restored by K+ channel blockers in ALS.
260 _ _ |a Heidelberg
|c 2021
|b EMBO Press
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520 _ _ |a 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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650 _ 7 |a ALS
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650 _ 7 |a CREB
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650 _ 7 |a hiPSC
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650 _ 7 |a motoneuron
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650 _ 7 |a synapse
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650 _ 2 |a Amyotrophic Lateral Sclerosis: drug therapy
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: genetics
|2 MeSH
650 _ 2 |a Animals
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650 _ 2 |a Humans
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650 _ 2 |a Induced Pluripotent Stem Cells
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650 _ 2 |a Mice
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650 _ 2 |a Motor Neurons
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650 _ 2 |a Neurodegenerative Diseases
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650 _ 2 |a Neuroprotective Agents
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700 1 _ |a Rajkumar, Sandeep
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700 1 _ |a Sommer, Daniel
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700 1 _ |a Freisem, Dennis
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700 1 _ |a Wirth, Alexander
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700 1 _ |a Aly, Amr
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700 1 _ |a Massa-López, David
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700 1 _ |a Olivieri, Andrea
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700 1 _ |a Torelli, Federica
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700 1 _ |a Ioannidis, Valentin
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700 1 _ |a Lipecka, Joanna
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700 1 _ |a Guerrera, Ida Chiara
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700 1 _ |a Zytnicki, Daniel
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700 1 _ |a Kabashi, Edor
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700 1 _ |a Mulaw, Medhanie A
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700 1 _ |a Roselli, Francesco
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700 1 _ |a Böckers, Tobias
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773 _ _ |a 10.15252/emmm.202013131
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