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

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 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.

Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation

“…Overexpression of various TDP-43 kinases in cell or animal models was shown to promote TDP-43 aggregation and neurotoxicity (Choksi et al, 2014;Liachko et al, 2014;Nonaka et al, 2016;Taylor et al, 2018). Based on these studies, inhibition of TDP-43 phosphorylation by kinase inhibitors has been proposed as a potential therapeutic strategy for ALS (Liachko et al, 2013;Martinez-Gonzalez et al, 2020;Salado et al, 2014). A possible explanation for the discrepant findings could be that kinase overexpression has pleiotropic effects that may cause TDP-43 aggregation and neurotoxicity independent of TDP-43 phosphorylation.…”

Phase Separation and Neurodegenerative Diseases: A Disturbance in the Force

“…One possibility is to target the enzymes responsible for the PTMs driving this transition. For example, inhibition of CK-1d responsible for TDP-43 phosphorylation (Martínez-Gonzá lez et al, 2020), inhibition of TDP-43 SUMOylation by anacardic acid (Maurel et al, 2020), or increase TDP-43 acetylation by activation of HSF1 (Wang et al, 2017) revert its aggregation, while maintaining its nuclear physiological localization in models for ALS. Similarly, inhibition of PARP-1/2, responsible for polyADP-ribosylation of TDP-43, by small molecules blocks the formation of cytoplasmic aggregates (McGurk et al, 2018).…”

Protein kinase inhibitors for amyotrophic lateral sclerosis therapy

“…More recently, compounds IGS2.7 and IGS2.37 ( Figure 1) have shown their ability to decrease TDP-43 phosphorylation in human cellular models derived from frontotemporal lobar degeneration (FTLD) patients (Alquezar et al, 2016) and ALS patients (Posa et al, 2019). Furthermore, the good pharmacokinetic profile of compound IGS2.7 motivated its study in the transgenic TDP-43 mice, showing motoneuron preservation, decrease of microglia activation and TDP-43 phosphorylation in spinal cord (Martinez-Gonzalez et al, 2020). Up to date, these inhibitors are still in preclinical trials for ALS; however, Pfizer completed two clinical Phase I studies with a CK-1δ/ε inhibitor, PF-05251749 (ClinicalTrials.gov Identifier: NCT02443740 and NCT02691702), which is being developed for irregular sleep-awake disorders in Parkinson's patients, showing good safety and tolerability, validating the safety of these therapeutic targets at a clinical level.…”