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

INTRODUCTION: TDP-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, su...

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Autores principales: Martinez-Gonzalez, Loreto, Cuevas, Eva P., Tosat-Bitrián, Carlota, Nozal, Vanesa, Gil, Carmen, Palomo, Valle, Martín-Requero, Ángeles, Martinez, Ana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10445132/
https://www.ncbi.nlm.nih.gov/pubmed/37621404
http://dx.doi.org/10.3389/fnmol.2023.1243277
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author Martinez-Gonzalez, Loreto
Cuevas, Eva P.
Tosat-Bitrián, Carlota
Nozal, Vanesa
Gil, Carmen
Palomo, Valle
Martín-Requero, Ángeles
Martinez, Ana
author_facet Martinez-Gonzalez, Loreto
Cuevas, Eva P.
Tosat-Bitrián, Carlota
Nozal, Vanesa
Gil, Carmen
Palomo, Valle
Martín-Requero, Ángeles
Martinez, Ana
author_sort Martinez-Gonzalez, Loreto
collection PubMed
description INTRODUCTION: TDP-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. METHODOLOGY: We 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. RESULTS: TDP-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. CONCLUSION: TTBK1 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.
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spelling pubmed-104451322023-08-24 TTBK1 and CK1 inhibitors restore TDP-43 pathology and avoid disease propagation in lymphoblast from Alzheimer’s disease patients Martinez-Gonzalez, Loreto Cuevas, Eva P. Tosat-Bitrián, Carlota Nozal, Vanesa Gil, Carmen Palomo, Valle Martín-Requero, Ángeles Martinez, Ana Front Mol Neurosci Neuroscience INTRODUCTION: TDP-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. METHODOLOGY: We 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. RESULTS: TDP-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. CONCLUSION: TTBK1 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. Frontiers Media S.A. 2023-08-09 /pmc/articles/PMC10445132/ /pubmed/37621404 http://dx.doi.org/10.3389/fnmol.2023.1243277 Text en Copyright © 2023 Martinez-Gonzalez, Cuevas, Tosat-Bitrián, Nozal, Gil, Palomo, Martín-Requero and Martinez. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Martinez-Gonzalez, Loreto
Cuevas, Eva P.
Tosat-Bitrián, Carlota
Nozal, Vanesa
Gil, Carmen
Palomo, Valle
Martín-Requero, Ángeles
Martinez, Ana
TTBK1 and CK1 inhibitors restore TDP-43 pathology and avoid disease propagation in lymphoblast from Alzheimer’s disease patients
title TTBK1 and CK1 inhibitors restore TDP-43 pathology and avoid disease propagation in lymphoblast from Alzheimer’s disease patients
title_full TTBK1 and CK1 inhibitors restore TDP-43 pathology and avoid disease propagation in lymphoblast from Alzheimer’s disease patients
title_fullStr TTBK1 and CK1 inhibitors restore TDP-43 pathology and avoid disease propagation in lymphoblast from Alzheimer’s disease patients
title_full_unstemmed TTBK1 and CK1 inhibitors restore TDP-43 pathology and avoid disease propagation in lymphoblast from Alzheimer’s disease patients
title_short TTBK1 and CK1 inhibitors restore TDP-43 pathology and avoid disease propagation in lymphoblast from Alzheimer’s disease patients
title_sort ttbk1 and ck1 inhibitors restore tdp-43 pathology and avoid disease propagation in lymphoblast from alzheimer’s disease patients
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10445132/
https://www.ncbi.nlm.nih.gov/pubmed/37621404
http://dx.doi.org/10.3389/fnmol.2023.1243277
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