TY  - JOUR
AU  - Catanese, Alberto
AU  - Rajkumar, Sandeep
AU  - Sommer, Daniel
AU  - Freisem, Dennis
AU  - Wirth, Alexander
AU  - Aly, Amr
AU  - Massa-López, David
AU  - Olivieri, Andrea
AU  - Torelli, Federica
AU  - Ioannidis, Valentin
AU  - Lipecka, Joanna
AU  - Guerrera, Ida Chiara
AU  - Zytnicki, Daniel
AU  - Ludolph, Albert
AU  - Kabashi, Edor
AU  - Mulaw, Medhanie A
AU  - Roselli, Francesco
AU  - Böckers, Tobias
TI  - Synaptic disruption and CREB-regulated transcription are restored by K+ channel blockers in ALS.
JO  - EMBO molecular medicine
VL  - 13
IS  - 7
SN  - 1757-4684
CY  - Heidelberg
PB  - EMBO Press
M1  - DZNE-2021-00861
SP  - e13131
PY  - 2021
AB  - 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.
KW  - Amyotrophic Lateral Sclerosis: drug therapy
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Animals
KW  - Humans
KW  - Induced Pluripotent Stem Cells
KW  - Mice
KW  - Motor Neurons
KW  - Neurodegenerative Diseases
KW  - Neuroprotective Agents
KW  - ALS (Other)
KW  - CREB (Other)
KW  - hiPSC (Other)
KW  - motoneuron (Other)
KW  - synapse (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:34125498
C2  - pmc:PMC8261490
DO  - DOI:10.15252/emmm.202013131
UR  - https://pub.dzne.de/record/155693
ER  -