c-Abl/TFEB Pathway Activation as a Common Pathogenic Mechanism in Lysosomal Storage Diseases: Therapeutic Potential of c-Abl Inhibitors

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dc.article.number611
dc.catalogadorgjm
dc.contributor.authorGuerra Vergara, Miguel Andrés
dc.contributor.authorCastro Salazar, Juan Francisco
dc.contributor.authorMoreno Torres, Antonio Daniel
dc.contributor.authorBalboa, Elisa
dc.contributor.authorMarugan, Juan J.
dc.contributor.authorÁlvarez Rojas, Alejandra
dc.contributor.authorZanlungo Matsuhiro, Silvana
dc.date.accessioned2025-05-28T15:37:23Z
dc.date.available2025-05-28T15:37:23Z
dc.date.issued2025
dc.description.abstractLysosomal storage diseases (LSDs) are characterized by the accumulation of undegraded substrates within lysosomes, often associated with oxidative stress and impaired lysosomal function. In this study, we investigate the role of the c-Abl/TFEB pathway in different LSDs: Gaucher, Niemann-Pick type A (NPA), and Niemann-Pick type C (NPC). Our findings identify c-Abl activation (p-c-Abl) as a common pathogenic mechanism in these disorders. We demonstrate that c-Abl phosphorylates TFEB at Tyr173, leading to its cytoplasmic retention. Using pharmacological models of Gaucher, NPA and NPC in SH-SY5Y neuronal cells and HeLa cells, we assess the effects of the c-Abl inhibitors Imatinib and Neurotinib, as well as the antioxidant α-Tocopherol (α-TOH), on TFEB nuclear translocation and p-c-Abl protein levels. Additionally, we explore the effects of c-Abl inhibitors in cholesterol accumulation in LSDs neuronal models. Our results show that treatment with c-Abl inhibitors or α-TOH promotes TFEB nuclear translocation, enhances lysosomal clearance, and reduces cholesterol accumulation in all three LSD models. These findings highlight the c-Abl/TFEB pathway as a potential therapeutic target for LSDs and potentially other neurodegenerative disorders associated with lysosomal dysfunction.
dc.fechaingreso.objetodigital2025-05-28
dc.format.extent17 páginas
dc.fuente.origenORCID
dc.identifier.doi10.3390/antiox14050611
dc.identifier.urihttps://doi.org/10.3390/antiox14050611
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/104500
dc.information.autorucEscuela de Medicina; Guerra Vergara, Miguel Andrés; S/I; 1251324
dc.information.autorucEscuela de Medicina; Castro Salazar, Juan Francisco; S/I; 8518
dc.information.autorucFacultad de Ciencias Biológicas; Moreno Torres, Antonio Daniel; S/I; 1066810
dc.information.autorucFacultad de Ciencias Biológicas; Álvarez Rojas, Alejandra; 0000-0002-8129-9280; 83681
dc.information.autorucEscuela de Medicina; Zanlungo Matsuhiro, Silvana; 0000-0001-8383-9829; 72650
dc.issue.numero5
dc.language.isoen
dc.nota.accesocontenido completo
dc.revistaAntioxidants
dc.rightsacceso abierto
dc.rights.licenseCC BY 4.0 Attribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectLysosomal storage diseases
dc.subjectNiemann-Pick
dc.subjectGaucher
dc.subjectc-Abl
dc.subjectTranscription factor EB
dc.subjectα-Tocopherol
dc.subjectNeurotinib
dc.subjectImatinib
dc.subject.ddc610
dc.subject.deweyMedicina y saludes_ES
dc.subject.ods03 Good health and well-being
dc.subject.odspa03 Salud y bienestar
dc.titlec-Abl/TFEB Pathway Activation as a Common Pathogenic Mechanism in Lysosomal Storage Diseases: Therapeutic Potential of c-Abl Inhibitors
dc.typeartículo
dc.volumen14
sipa.codpersvinculados1251324
sipa.codpersvinculados8518
sipa.codpersvinculados1066810
sipa.codpersvinculados83681
sipa.codpersvinculados72650
sipa.trazabilidadORCID;2025-05-26
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