Yañez, M.J.Campos, F.Marín, T.Klein, AndrésFuterman, A. H.Alvarez, A. R.Zanlungo, S.2022-04-282022-04-282021Yañez 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.https://doi.org/ 10.1016/j.bbadis.2021.166089http://hdl.handle.net/11447/6031Gaucher 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 GDenDeathGaucher disease (GD)Lysosomal storage disorders (LSD)NecroptosisReceptor interacting serine/threonine kinase 3 (RIPK3)Tyrosine kinase c-AblArticle