A multilevel screening pipeline in zebrafish identifies therapeutic drugs for GAN.

Autor: Lescouzères L; ERC Team, NeuroMyoGene Insitute - Now PGNM, Inserm U1315, CNRS UMR5261, University of Lyon 1, Lyon, France., Hassen-Khodja C; Montpellier Ressources Imagerie, BioCampus, University of Montpellier, CNRS, INSERM, Montpellier, France., Baudot A; Aix Marseille Univ, INSERM, MMG, Marseille Medical Genetics, CNRS, Marseille, France., Bordignon B; Montpellier Ressources Imagerie, BioCampus, University of Montpellier, CNRS, INSERM, Montpellier, France., Bomont P; ERC Team, NeuroMyoGene Insitute - Now PGNM, Inserm U1315, CNRS UMR5261, University of Lyon 1, Lyon, France.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2023 Jul 10; Vol. 15 (7), pp. e16267. Date of Electronic Publication: 2023 May 05.
DOI: 10.15252/emmm.202216267
Abstrakt: Giant axonal neuropathy (GAN) is a fatal neurodegenerative disorder for which there is currently no treatment. Affecting the nervous system, GAN starts in infancy with motor deficits that rapidly evolve toward total loss of ambulation. Using the gan zebrafish model that reproduces the loss of motility as seen in patients, we conducted the first pharmacological screening for the GAN pathology. Here, we established a multilevel pipeline to identify small molecules restoring both the physiological and the cellular deficits in GAN. We combined behavioral, in silico, and high-content imaging analyses to refine our Hits to five drugs restoring locomotion, axonal outgrowth, and stabilizing neuromuscular junctions in the gan zebrafish. The postsynaptic nature of the drug's cellular targets provides direct evidence for the pivotal role the neuromuscular junction holds in the restoration of motility. Our results identify the first drug candidates that can now be integrated in a repositioning approach to fasten therapy for the GAN disease. Moreover, we anticipate both our methodological development and the identified hits to be of benefit to other neuromuscular diseases.
(© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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