| First Author | Yañez MJ | Year | 2021 |
| Journal | Biochim Biophys Acta Mol Basis Dis | Volume | 1867 |
| Issue | 5 | Pages | 166089 |
| PubMed ID | 33549745 | Mgi Jnum | J:304097 |
| Mgi Id | MGI:6515375 | Doi | 10.1016/j.bbadis.2021.166089 |
| Citation | Yanez MJ, et al. (2021) c-Abl activates RIPK3 signaling in Gaucher disease. Biochim Biophys Acta Mol Basis Dis 1867(5):166089 |
| abstractText | Gaucher disease (GD) is caused by homozygous mutations in the GBA1 gene, which encodes the lysosomal beta-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. |
