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

Autor: Catanese A; Institute of Anatomy and Cell Biology, Ulm University School of Medicine, Ulm, Germany., Rajkumar S; Institute of Anatomy and Cell Biology, Ulm University School of Medicine, Ulm, Germany., Sommer D; Institute of Anatomy and Cell Biology, Ulm University School of Medicine, Ulm, Germany., Freisem D; Institute of Anatomy and Cell Biology, Ulm University School of Medicine, Ulm, Germany., Wirth A; Institute of Anatomy and Cell Biology, Ulm University School of Medicine, Ulm, Germany., Aly A; Institute of Anatomy and Cell Biology, Ulm University School of Medicine, Ulm, Germany., Massa-López D; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ulm site, Ulm, Germany., Olivieri A; Institute of Anatomy and Cell Biology, Ulm University School of Medicine, Ulm, Germany., Torelli F; Institute of Anatomy and Cell Biology, Ulm University School of Medicine, Ulm, Germany., Ioannidis V; Institute of Anatomy and Cell Biology, Ulm University School of Medicine, Ulm, Germany., Lipecka J; Proteomics platform Necker, INSERM US24/CNRS UMS3633, Université de Paris - Structure Fédérative de Recherche Necker, Paris, France., Guerrera IC; Proteomics platform Necker, INSERM US24/CNRS UMS3633, Université de Paris - Structure Fédérative de Recherche Necker, Paris, France., Zytnicki D; SPPIN - Saints-Pères Paris Institute for the Neurosciences, CNRS, Université de Paris, Paris, Paris., Ludolph A; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ulm site, Ulm, Germany.; Department of Neurology, Ulm University School of Medicine, Ulm, Germany., Kabashi E; Institute of Translational Research for Neurological Disorders, INSERM UMR 1163, Imagine Institute, Paris, France., Mulaw MA; Internal Medicine I and Institute of Molecular Medicine and Stem Cell Aging, Medical Faculty, University Hospital Ulm, University of Ulm University, Ulm, Germany., Roselli F; Institute of Anatomy and Cell Biology, Ulm University School of Medicine, Ulm, Germany.; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ulm site, Ulm, Germany.; Department of Neurology, Ulm University School of Medicine, Ulm, Germany., Böckers TM; Institute of Anatomy and Cell Biology, Ulm University School of Medicine, Ulm, Germany.; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ulm site, Ulm, Germany.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2021 Jul 07; Vol. 13 (7), pp. e13131. Date of Electronic Publication: 2021 Jun 14.
DOI: 10.15252/emmm.202013131
Abstrakt: 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.
(© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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