| First Author | Ko VI | Year | 2024 |
| Journal | Acta Neuropathol Commun | Volume | 12 |
| Issue | 1 | Pages | 187 |
| PubMed ID | 39633494 | Mgi Jnum | J:360751 |
| Mgi Id | MGI:7785732 | Doi | 10.1186/s40478-024-01902-z |
| Citation | Ko VI, et al. (2024) CK1delta/epsilon-mediated TDP-43 phosphorylation contributes to early motor neuron disease toxicity in amyotrophic lateral sclerosis. Acta Neuropathol Commun 12(1):187 |
| abstractText | Hyperphosphorylated TDP-43 aggregates in the cytoplasm of motor neurons is a neuropathological signature of amyotrophic lateral sclerosis (ALS). These aggregates have been proposed to possess a toxic disease driving role in ALS pathogenesis and progression, however, the contribution of phosphorylation to TDP-43 aggregation and ALS disease mechanisms remains poorly understood. We've previously shown that CK1delta and CK1epsilon phosphorylate TDP-43 at disease relevant sites, and that genetic reduction and chemical inhibition could reduce phosphorylated TDP-43 (pTDP-43) levels in cellular models. In this study, we advanced our findings into the hTDP-43-DeltaNLS in vivo mouse model of ALS and TDP-43 proteinopathy. This mouse model possesses robust disease-relevant features of ALS, including TDP-43 nuclear depletion, cytoplasmic pTDP-43 accumulation, motor behavior deficits, and shortened survival. We tested the effect of homozygous genetic deletion of Csnk1e in the hTDP-43-DeltaNLS mouse model and observed a delay in the formation of pTDP-43 without significant ultimate rescue of TDP-43 proteinopathy or disease progression. Homozygous genetic deletion of Csnk1d is lethal in mice, and we were unable to test the role of CK1delta alone. We then targeted both CK1delta and CK1epsilon kinases by way of CK1delta/epsilon-selective PF-05236216 inhibitor in the hTDP-43-DeltaNLS mouse model, reasoning that inhibiting CK1epsilon alone would be insufficient as shown by our Csnk1e knockout mouse model study. Treated mice demonstrated reduced TDP-43 phosphorylation, lowered Nf-L levels, and improved survival in the intermediate stages. The soluble TDP-43 may have been more amenable to the inhibitor treatment than insoluble TDP-43. However, the treatments did not result in improved functional measurements or in overall survival. Our results demonstrate that phosphorylation contributes to neuronal toxicity and suggest CK1delta/epsilon inhibition in combination with other therapies targeting TDP-43 pathology could potentially provide therapeutic benefit in ALS. |
