c-Abl activates RIPK3 signaling in Gaucher disease

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dc.catalogadoryvc
dc.contributor.authorYañez Henríquez, María José
dc.contributor.authorCampos, F.
dc.contributor.authorMarín Marín, Tamara Alejandra
dc.contributor.authorKlein Posternack, Andrés David
dc.contributor.authorFuterman, A. H.
dc.contributor.authorÁlvarez, Alejandra R.
dc.contributor.authorZanlungo Matsuhiro, Silvana
dc.date.accessioned2024-06-06T19:19:44Z
dc.date.available2024-06-06T19:19:44Z
dc.date.issued2021
dc.description.abstractGaucher disease (GD) is caused by homozygous mutations in the GBA1 gene, which encodes the lysosomal β-glucosidase (GBA) enzyme. GD affects several organs and tissues, including the brain in certain variants of the disease. Heterozygous GBA1 variants are a major genetic risk factor for developing Parkinson's disease. The RIPK3 kinase is relevant in GD and its deficiency improves the neurological and visceral symptoms in a murine GD model. RIPK3 mediates necroptotic-like cell death: it is unknown whether the role of RIPK3 in GD is the direct induction of necroptosis or if it has a more indirect function by mediating necrosis-independent. Also, the mechanisms that activate RIPK3 in GD are currently unknown. In this study, we show that c-Abl tyrosine kinase participates upstream of RIPK3 in GD. We found that the active, phosphorylated form of c-Abl is increased in several GD models, including patient's fibroblasts and GBA null mice. Furthermore, its pharmacological inhibition with the FDA-approved drug Imatinib decreased RIPK3 signaling. We found that c-Abl interacts with RIPK3, that RIPK3 is phosphorylated at a tyrosine site, and that this phosphorylation is reduced when c-Abl is inhibited. Genetic ablation of c-Abl in neuronal GD and GD mice models significantly reduced RIPK3 activation and MLKL downstream signaling. These results showed that c-Abl signaling is a new upstream pathway that activates RIPK3 and that its inhibition is an attractive therapeutic approach for the treatment of GD.
dc.fuente.origenORCID
dc.identifier.doi10.1016/j.bbadis.2021.166089
dc.identifier.urihttps://doi.org/10.1016/j.bbadis.2021.166089
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/86568
dc.information.autorucFacultad de Ciencias Biológicas;Yañez Henríquez, María José;S/I;197587
dc.information.autorucEscuela de Medicina;Marín Marín, Tamara Alejandra;S/I;249923
dc.information.autorucFacultad de Ciencias Biológicas;Klein Posternack, Andrés David;S/I;2966
dc.information.autorucEscuela de Medicina; Zanlungo Matsuhiro, Silvana; 0000-0001-8383-9829; 72650
dc.language.isoen
dc.nota.accesocontenido parcial
dc.rightsacceso restringido
dc.subject.ddc610
dc.subject.deweyMedicina y saludes_ES
dc.titlec-Abl activates RIPK3 signaling in Gaucher disease
dc.typeartículo
sipa.codpersvinculados72650
sipa.trazabilidadORCID;2024-06-03
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