RT Journal Article
T1 Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment
A1 Martínez González, Loreto
A1 Rodríguez Cueto, Carmen Aurora
A1 Cabezudo, Diego
A1 Bartolomé, Fernando
A1 Andrés-Benito, Pol
A1 Ferrer, Isidro   Eva de Lago
A1 Gil, Carmen
A1 Martín-Requero, Ángeles
A1 Fernández Ruiz, José Javier
A1 Martínez, Ana
A1 de lago femia, 
A1 Lago Femia, Eva De
AB 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 the benefits in the preservation of spinal motor neurons and point to the relevance of CK-1δ inhibitors in a future disease-modifying treatment for ALS.
PB Nature
YR 2020
FD 2020-03-10
LK https://hdl.handle.net/20.500.14352/113190
UL https://hdl.handle.net/20.500.14352/113190
LA eng
NO Martínez-González L, Rodríguez-Cueto C, Cabezudo D, Bartolomé F, Andrés-Benito P, Ferrer I, Gil C, Martín-Requero Á, Fernández-Ruiz J, Martínez A, de Lago E. Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment. Sci Rep. 2020 Mar 10;10(1):4449. doi: 10.1038/s41598-020-61265-y. PMID: 32157143; PMCID: PMC7064575.
NO Este trabajo fue financiado por MINECO (subvención SAF2015-68580-C2-1-R a EdL, JFR y CRC, SAF2016-76693-R a AM y CTQ2015-66313-R a AMR), CIBERNED (CB06/05/0089 a CRC, JFR y EdL y CB18/05/00040 a AMR y AM), Comunidad de Madrid (subvención B2017/BMD3813 ELA-Madrid) y fondos estructurales de la UE (FSE y FEDER).
DS Docta Complutense
RD 17 abr 2025