c-Abl activates RIPK3 signaling in Gaucher disease
M J Yañez1, F Campos2, T Marín2
1Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile; School of Medical Technology, Health Sciences Faculty, Universidad San Sebastian, Sede Los Leones, Santiago, Chile.
Biochimica Et Biophysica Acta. Molecular Basis of Disease
|February 7, 2021
Summary
Gaucher disease (GD) involves the GBA1 gene. This study reveals c-Abl tyrosine kinase activates RIPK3 signaling in GD, suggesting c-Abl inhibition as a potential therapeutic strategy for GD.
Area of Science:
- Biochemistry
- Genetics
- Cell Biology
Background:
- Gaucher disease (GD) stems from GBA1 gene mutations, impacting the GBA enzyme and affecting multiple organs, including the brain.
- RIPK3 kinase plays a role in GD, with its deficiency improving symptoms in mouse models, but its activation mechanisms in GD remain unclear.
- Heterozygous GBA1 variants are linked to Parkinson's disease risk.
Purpose of the Study:
- To investigate the upstream mechanisms activating RIPK3 in Gaucher disease.
- To explore the role of c-Abl tyrosine kinase in RIPK3 activation in GD.
- To evaluate c-Abl inhibition as a therapeutic strategy for GD.
Main Methods:
- Assessed active, phosphorylated c-Abl levels in GD patient fibroblasts and GBA null mice.
- Investigated the interaction between c-Abl and RIPK3, including RIPK3 phosphorylation.
- Utilized pharmacological inhibition of c-Abl with Imatinib and genetic ablation of c-Abl in GD models.
Main Results:
- Active c-Abl was elevated in various GD models.
- c-Abl inhibition reduced RIPK3 signaling and RIPK3 tyrosine phosphorylation.
- Genetic ablation of c-Abl decreased RIPK3 activation and downstream MLKL signaling.
Conclusions:
- c-Abl tyrosine kinase acts upstream of RIPK3 in Gaucher disease pathogenesis.
- c-Abl signaling pathway is identified as a novel activator of RIPK3 in GD.
- Inhibiting c-Abl presents a promising therapeutic avenue for treating Gaucher disease.
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