Dataset Information

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

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.

SUBMITTER: Catanese A

PROVIDER: S-EPMC8261490 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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

Catanese Alberto A Rajkumar Sandeep S Sommer Daniel D Freisem Dennis D Wirth Alexander A Aly Amr A Massa-López David D Olivieri Andrea A Torelli Federica F Ioannidis Valentin V Lipecka Joanna J Guerrera Ida Chiara IC Zytnicki Daniel D Ludolph Albert A Kabashi Edor E Mulaw Medhanie A MA Roselli Francesco F Böckers Tobias M TM

EMBO molecular medicine 20210614 7

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 ...[more]

PMID: 34125498

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

Publications

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

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Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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