dc.creator | Yañez, M.J. | |
dc.creator | Campos, F. | |
dc.creator | Marín, T. | |
dc.creator | Klein, Andrés | |
dc.creator | Futerman, A. H. | |
dc.creator | Alvarez, A. R. | |
dc.creator | Zanlungo, S. | |
dc.date.accessioned | 2022-04-28T16:48:21Z | |
dc.date.accessioned | 2023-05-19T14:46:55Z | |
dc.date.available | 2022-04-28T16:48:21Z | |
dc.date.available | 2023-05-19T14:46:55Z | |
dc.date.created | 2022-04-28T16:48:21Z | |
dc.date.issued | 2021 | |
dc.identifier | Yañez 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. | |
dc.identifier | https://doi.org/ 10.1016/j.bbadis.2021.166089 | |
dc.identifier | http://hdl.handle.net/11447/6031 | |
dc.identifier.uri | https://repositorioslatinoamericanos.uchile.cl/handle/2250/6301761 | |
dc.description.abstract | Gaucher 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.language | en | |
dc.subject | Death | |
dc.subject | Gaucher disease (GD) | |
dc.subject | Lysosomal storage disorders (LSD) | |
dc.subject | Necroptosis | |
dc.subject | Receptor interacting serine/threonine kinase 3 (RIPK3) | |
dc.subject | Tyrosine kinase c-Abl | |
dc.title | c-Abl activates RIPK3 signaling in Gaucher disease | |
dc.type | Article | |