| First Author | Martínez-González L | Year | 2020 |
| Journal | Sci Rep | Volume | 10 |
| Issue | 1 | Pages | 4449 |
| PubMed ID | 32157143 | Mgi Jnum | J:293888 |
| Mgi Id | MGI:6407330 | Doi | 10.1038/s41598-020-61265-y |
| Citation | Martinez-Gonzalez L, et al. (2020) Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1delta kinase inhibitor treatment. Sci Rep 10(1):4449 |
| abstractText | 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-1delta (protein casein kinase-1delta) is able to phosphorylate TDP-43. Here, the preclinical efficacy of a benzothiazole-based CK-1delta 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-1delta 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-1delta inhibition with IGS-2.7, which may explain the benefits in the preservation of spinal motor neurons and point to the relevance of CK-1delta inhibitors in a future disease-modifying treatment for ALS. |
