CK1δ/ε-mediated TDP-43 phosphorylation contributes to early motor neuron disease toxicity in amyotrophic lateral sclerosis.

IF 6.2 2区 医学 Q1 NEUROSCIENCES
Vivian I Ko, Kailee Ong, Deborah Y Kwon, Xueying Li, Alicia Pietrasiewicz, James S Harvey, Mukesh Lulla, Guruharsha Bhat, Don W Cleveland, John M Ravits
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引用次数: 0

Abstract

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 CK1δ and CK1ε 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-ΔNLS 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-ΔNLS 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 CK1δ alone. We then targeted both CK1δ and CK1ε kinases by way of CK1δ/ε-selective PF-05236216 inhibitor in the hTDP-43-ΔNLS mouse model, reasoning that inhibiting CK1ε 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 CK1δ/ε inhibition in combination with other therapies targeting TDP-43 pathology could potentially provide therapeutic benefit in ALS.

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来源期刊
Acta Neuropathologica Communications
Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine
CiteScore
11.20
自引率
2.80%
发文量
162
审稿时长
8 weeks
期刊介绍: "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.
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