Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment

Scientific Reports
Loreto Martínez-GonzálezEva de Lago

Abstract

Pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating disease where no treatment exists, involves the compartmentalization of the nuclear protein TDP-43 (TAR DNA-binding protein 43) in the cytoplasm which is promoted by its aberrant phosphorylation and others posttranslational modifications. Recently, it was reported that CK-1δ (protein casein kinase-1δ) is able to phosphorylate TDP-43. Here, the preclinical efficacy of a benzothiazole-based CK-1δ inhibitor IGS-2.7, both in a TDP-43 (A315T) transgenic mouse and in a human cell-based model of ALS, is shown. Treatment with IGS-2.7 produces a significant preservation of motor neurons in the anterior horn at lumbar level, a decrease in both astroglial and microglial reactivity in this area, and in TDP-43 phosphorylation in spinal cord samples. Furthermore, the recovery of TDP-43 homeostasis (phosphorylation and localization) in a human-based cell model from ALS patients after treatment with IGS-2.7 is also reported. Moreover, we have shown a trend to increase in CK-1δ mRNA in spinal cord and significantly in frontal cortex of sALS cases. All these data show for the first time the in vivo modulation of TDP-43 toxicity by CK-1δ inhibition with IGS-2.7, which may explain ...Continue Reading

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Citations

May 30, 2020·British Journal of Pharmacology·Emanuele Buratti
Aug 2, 2020·British Journal of Pharmacology·Valle PalomoAna Martinez
Apr 4, 2021·International Journal of Molecular Sciences·Isabel Lastres-BeckerÁngeles Martin-Requero
Oct 14, 2020·Developmental Cell·Aurélie ZbindenMagdalini Polymenidou
May 26, 2021·GeroScience·Randall J EckNicole F Liachko
Aug 28, 2021·International Journal of Molecular Sciences·Loreto Martínez-GonzálezAna Martínez
Sep 4, 2021·Annals of Neurology·Erika B VillanuevaShohreh Issazadeh-Navikas
Nov 3, 2021·The Journal of Cell Biology·Xue DengYanshan Fang

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Methods Mentioned

BETA
transgenic
density-gradient centrifugation
Protein Assay
PCR

Software Mentioned

Image J
Volocity
Graph Pad
Quantity One

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