c-Abl activates RIPK3 signaling in Gaucher disease

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dc.contributor.authorYañez, M.J.
dc.contributor.authorCampos, F.
dc.contributor.authorMarín, T.
dc.contributor.authorKlein, Andrés
dc.contributor.authorFuterman, A. H.
dc.contributor.authorAlvarez, A. R.
dc.contributor.authorZanlungo, S.
dc.date.accessioned2022-04-28T16:48:21Z
dc.date.available2022-04-28T16:48:21Z
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 GDes
dc.description.versionVersión Publicadaes
dc.identifier.citationYañez MJ, Campos F, Marín T, Klein AD, Futerman AH, Alvarez AR, Zanlungo S. c-Abl activates RIPK3 signaling in Gaucher disease. Biochim Biophys Acta Mol Basis Dis. 2021 May 1;1867(5):166089. doi: 10.1016/j.bbadis.2021.166089. Epub 2021 Feb 4.es
dc.identifier.urihttps://doi.org/ 10.1016/j.bbadis.2021.166089es
dc.identifier.urihttp://hdl.handle.net/11447/6031
dc.language.isoenes
dc.subjectDeathes
dc.subjectGaucher disease (GD)es
dc.subjectLysosomal storage disorders (LSD)es
dc.subjectNecroptosises
dc.subjectReceptor interacting serine/threonine kinase 3 (RIPK3)es
dc.subjectTyrosine kinase c-Ables
dc.titlec-Abl activates RIPK3 signaling in Gaucher diseasees
dc.typeArticlees
dcterms.sourceBiochimica et Biophysica Acta (BBA) - Molecular Basis of Diseasees

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