TTBK1 and CK1 inhibitors restore TDP-43 pathology and avoid disease propagation in lymphoblast from Alzheimer’s disease patients

Frontiers in Molecular Neuroscience

Neuroscience

Carmen Gil¹  Ángeles Martín-Requero²  Eva P. Cuevas²  Ana Martinez²  Loreto Martinez-Gonzalez²  Carlota Tosat-Bitrián²  Vanesa Nozal²  Valle Palomo³ 

[1] Centro de Investigaciones Biológicas “Margarita Salas”-CSIC, Madrid, Spain;Centro de Investigaciones Biológicas “Margarita Salas”-CSIC, Madrid, Spain;Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain;Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain;Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA-Nanociencia), Madrid, Spain;

关键词: TDP-43 pathology;    Alzheimer’s disease;    CK1 inhibitor;    TTBK1 inhibitor;    drug discovery;   

DOI  :  10.3389/fnmol.2023.1243277

 received in 2023-06-23, accepted in 2023-07-24,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionTDP-43 proteinopathy in Alzheimer’s disease (AD) patients is recently emerging as a relevant pathomolecular event that may have been overlooked. Recent results in immortalized lymphocytes from AD patients have shown not only an increase of post-translational modifications in TDP-43, such as hyperphosphorylation and fragmentation, but also its prionic behaviour and cell-to-cell disease transmission. With the main goal to advance therapeutic interventions, we present in this work different kinase inhibitors with potential to restore this pathological mechanism.MethodologyWe have used immortalized lymphocytes from healthy controls and AD severe patients to evaluate the correction of TDP-43 pathology after the treatment with previously synthetized TTBK1 and CK1 inhibitors. Moreover we used the conditioned mediums of these cells to perform different disease propagation experiments.ResultsTDP-43 pathology observed in lymphoblasts from severe AD patients is reduced after the treatment with TTBK1 and CK1 inhibitors (decreasing phosphorylation and increasing nuclear localisation), Furthermore, the significant increase in TDP-43 phosphorylation, cytoplasmic accumulation and aberrant F-actin protrusions (TNT-like structures) observed in control cells growing in CM from AD lymphoblasts were abolished when the CM from AD lymphoblasts treated with previously reported TTBK1 and CK1 inhibitors were used. In addition, the cytosolic transport mediated by molecular motors of the receptor cells was altered with the induced TDP-43 pathology, but it was not produced with the abovementioned pretreated CMs.ConclusionTTBK1 and CK1 inhibitors, specially VNG1.47 and IGS2.7 compounds, restore TDP-43 pathology and avoid cell-to-cell propagation in immortalized lymphocytes from AD patients, being excellent candidates for the future therapy of this prevalent and devastating disease.

【 授权许可】

Unknown   
Copyright © 2023 Martinez-Gonzalez, Cuevas, Tosat-Bitrián, Nozal, Gil, Palomo, Martín-Requero and Martinez.

【 图 表 】

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