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oai:docta.ucm.es:20.500.14352/1131902025-08-07T17:10:59Zcom_20.500.14352_14col_20.500.14352_15

Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment Martínez González, Loreto Rodríguez Cueto, Carmen Aurora Cabezudo, Diego Bartolomé, Fernando Andrés-Benito, Pol Ferrer, Isidro Eva de Lago Gil, Carmen Martín-Requero, Ángeles Fernández Ruiz, José Javier Martínez, Ana de lago femia Lago Femia, Eva De 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. 2025-01-08T08:20:18Z 2025-01-08T08:20:18Z 2025-01-08T08:20:18Z 2020 journal article https://hdl.handle.net/20.500.14352/113190 XXXX-XXXX 10.1038/s41598-020-61265-y 2045-2322 eng 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. open access Nature