Dynactin1 depletion leads to neuromuscular synapse instability and functional abnormalities

Autor: Bercier, Valérie, Hubbard, Jeffrey M., Fidelin, Kevin, Duroure, Karine, Auer, Thomas O., Revenu, Céline, Wyart, Claire, Del Bene, Filippo
Přispěvatelé: Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University [New York], Université de Lausanne (UNIL), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne = University of Lausanne (UNIL), Gestionnaire, Hal Sorbonne Université
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Molecular Neurodegeneration, Vol 14, Iss 1, Pp 1-22 (2019)
Molecular Neurodegeneration
Molecular Neurodegeneration, BioMed Central, 2019, 14 (1), pp.27. ⟨10.1186/s13024-019-0327-3⟩
Molecular Neurodegeneration, 2019, 14 (1), pp.27. ⟨10.1186/s13024-019-0327-3⟩
Molecular neurodegeneration, vol. 14, no. 1, pp. 27
ISSN: 1750-1326
Popis: Background Dynactin subunit 1 is the largest subunit of the dynactin complex, an activator of the molecular motor protein complex dynein. Reduced levels of DCTN1 mRNA and protein have been found in sporadic amyotrophic lateral sclerosis (ALS) patients, and mutations have been associated with disease, but the role of this protein in disease pathogenesis is still unknown. Methods We characterized a Dynactin1a depletion model in the zebrafish embryo and combined in vivo molecular analysis of primary motor neuron development with live in vivo axonal transport assays in single cells to investigate ALS-related defects. To probe neuromuscular junction (NMJ) function and organization we performed paired motor neuron-muscle electrophysiological recordings and GCaMP calcium imaging in live, intact larvae, and the synapse structure was investigated by electron microscopy. Results Here we show that Dynactin1a depletion is sufficient to induce defects in the development of spinal cord motor neurons and in the function of the NMJ. We observe synapse instability, impaired growth of primary motor neurons, and higher failure rates of action potentials at the NMJ. In addition, the embryos display locomotion defects consistent with NMJ dysfunction. Rescue of the observed phenotype by overexpression of wild-type human DCTN1-GFP indicates a cell-autonomous mechanism. Synaptic accumulation of DCTN1-GFP, as well as ultrastructural analysis of NMJ synapses exhibiting wider synaptic clefts, support a local role for Dynactin1a in synaptic function. Furthermore, live in vivo analysis of axonal transport and cytoskeleton dynamics in primary motor neurons show that the phenotype reported here is independent of modulation of these processes. Conclusions Our study reveals a novel role for Dynactin1 in ALS pathogenesis, where it acts cell-autonomously to promote motor neuron synapse stability independently of dynein-mediated axonal transport. Electronic supplementary material The online version of this article (10.1186/s13024-019-0327-3) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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