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Título: | Casein kinase 1 inhibitor avoids TDP-43 pathology propagation in a patient-derived cellular model of amyotrophic lateral sclerosis |
Autor: | Cuevas, Eva P. CSIC ORCID ; Martínez-González, Loreto CSIC ORCID ; Gordillo, Clara; Tosat-Bitrian, Carlota CSIC ORCID ; Pérez de la Lastra, Carmen; Sáenz, Amets; Gil, Carmen CSIC ORCID ; Palomo, Valle CSIC ORCID ; Martín-Requero, Ángeles CSIC ORCID ; Martínez Gil, Ana CSIC ORCID | Palabras clave: | Amyotrophic lateral sclerosis TDP-43 CK-1 inhibitor Benzothiazole IGS2.17 Cell-to-cell disease propagation Extracellular vesicles |
Fecha de publicación: | mar-2024 | Editor: | Elsevier | Citación: | Neurobiology of Disease 192: 106430 (2024) | Resumen: | Amyotrophic lateral sclerosis is a fatal neurodegenerative disease without a cure to reverse its progression. Its main hallmark is the nuclear protein TDP-43, which undergoes different post-translational modifications leading to a loss of function in the nucleus and an increase in toxicity in the cytoplasm. Previous reports have indicated that pathogenic TDP-43 exhibits prion-like propagation in various contexts. With the aim of advancing therapeutics focused on preventing the propagation of TDP-43 pathology, we studied the potential role of pathogenic TDP-43 in lymphoblasts from sporadic ALS patients. We used lymphoblastoid cell lines from sporadic ALS patients as a source of pathogenic forms of TDP-43, and healthy human cells (lymphoblasts, myoblasts, neuroblastoma SH-SY5Y, or osteosarcoma U2OS) as recipient cells to investigate the seeding and spread of TDP-43 proteinopathy. Furthermore, we evaluated the potential of targeting TDP-43 phosphorylation with a CK-1 inhibitor to prevent the propagation of the pathology. The results presented herein indicate that pathogenic forms of TDP-43 are secreted into the extracellular medium of sporadic ALS lymphoblasts and could be transported by extracellular vesicles, spreading TDP-43 pathology to healthy cells. Moreover, tunneling nanotubes have also been discovered in pathological cells and may be involved in the transport of TDP-43. Interestingly, targeting TDP-43 phosphorylation with an in-house designed CK-1 inhibitor (IGS2.7) was sufficient to halt TDP-43 pathology transmission, in addition to its known effects on restoring the homeostasis of TDP-43 protein in patients-derived cells. | Descripción: | 16 p.-10 fig.-2 tab. | Versión del editor: | https://doi.org/10.1016/j.nbd.2024.106430 | URI: | http://hdl.handle.net/10261/347697 | DOI: | 10.1016/j.nbd.2024.106430 | ISSN: | 0969-9961 |
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Neurobiology of Disease_Cuevas_2024.pdf | Artículo principal | 14,29 MB | Adobe PDF | Visualizar/Abrir |
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