Browsing by Author "Marín Marín, Tamara Alejandra"
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- ItemC-ABL kinase in Niemann Pick type a disease : its implication in the pathogenic mechanisms leading to autophagic flux alterations and neurodegeneration.(2020) Marín Marín, Tamara Alejandra; Zanlungo Matsuhiro, Silvana; Pontificia Universidad Católica de Chile. Facultad de MedicinaNiemann-Pick type A (NPA) disease is a fatal lysosomal neurodegenerative and autosomal recessive disorder. It is characterized by deficiency in acid sphingomyelinase (ASM) and accumulation of sphingomyelin and cholesterol in lysosomes. Unfortunately, there is no cure for patients who die between 2-3 years of age. Previously we described that the c-Abl proapoptotic signaling pathway is key in neuronal death in different neurodegenerative diseases, including lysosomal disorders. Furthermore, recent studies show a role for c-Abl in autophagy and cellular clearance, processes that depend on the lysosome, and are essential for keeping cellular homeostasis. Indeed, autophagy dysfunctions are involved in different pathologies, including neurodegenerative diseases. Considering these antecedents, we propose to evaluate if c-Abl is hyperactivated and modulates autophagy and cellular clearance in NPA disease. The hypothesis of this thesis is that c-Abl hyperactivation blocks the autophagy flux contributing to the neuronal pathogenesis in Niemann Pick type A disease. Our general aim is to determine if c-Abl hyperactivation blocks the autophagy flux contributing to the neuronal pathogenesis in Niemann Pick type A disease. The specific aims are: 1) To determine if the c-Abl signaling pathway is hyperactivated and participates in NPA disease neurodegeneration and 2) To evaluate if hyperactivation of the c-Abl signaling pathway inhibits autophagy flux in NPA models. We used several NPA models including; fibroblasts from NPA patients, Neural Stem Cells derived from these fibroblasts and a NPA mouse. In these models we modulated c-Abl activity and evaluated cell death, cerebellar inflammation and autophagy flux. Our results show that: i) c-Abl is hyperactivated and contributes to the neurodegeneration in in vitro and in vivo NPA models; ii) There are lysosomal and autophagy alterations in NPA models; iii) c-Abl inhibition induces autophagy and decreases lipid accumulation in in vitro NPA models; iv) c-Abl inhibition decreases neuronal death and inflammation at the cerebellum and improves locomotor function in NPA mice and v) the downregulated genes in NPA fibroblasts increase their expression upon Imatinib treatment. Interestingly, these genes are direct or indirectly related with autophagy. These results give new antecedents to understand the role of c-Abl in autophagy regulation and its contribution to the NPA disease pathogenic mechanisms. Additionally, these results allow us to propose c-Abl inhibitors as a therapeutic option for this disease.
- ItemThe c-Abl/p73 pathway induces neurodegeneration in a Parkinson's disease model(2022) Marín Marín, Tamara Alejandra; Valls Jimenez, Cristián Felipe; Jerez C.; Huerta T.; Elgueta D.; Vidal R.L.; Alvaréz Rojas, Alejandra Beatriz; Cancino, GonzaloParkinson's disease is the second most common neurodegenerative disorder. Although it is clear that dopaminergic neurons degenerate, the underlying molecular mechanisms are still unknown, and thus, successful treatment is still elusive. One pro-apoptotic pathway associated with several neurodegenerative diseases is the tyrosine kinase c-Abl and its target p73. Here, we evaluated the contribution of c-Abl and p73 in the degeneration of dopaminergic neurons induced by the neurotoxin 6-hydroxydopamine as a model for Parkinson's disease. First, we found that in SH-SY5Y cells treated with 6-hydroxydopamine, c-Abl and p73 phosphorylation levels were up-regulated. Also, we found that the pro-apoptotic p73 isoform TAp73 was up-regulated. Then, to evaluate whether c-Abl tyrosine kinase activity is necessary for 6-hydroxydopamine-induced apoptosis, we co-treated SH-SY5Y cells with 6-hydroxydopamine and Imatinib, a c-Abl specific inhibitor, observing that Imatinib prevented p73 phosphorylation, TAp73 up-regulation, and protected SH-SY5Y cells treated with 6-hydroxydopamine from apoptosis. Interestingly, this observation was confirmed in the c-Abl conditional null mice, where 6-hydroxydopamine stereotaxic injections induced a lesser reduction of dopaminergic neurons than in the wild-type mice significantly. Finally, we found that the intraperitoneal administration of Imatinib prevented the death of dopaminergic neurons induced by injecting 6-hydroxydopamine stereotaxically in the mice striatum. Thus, our findings support the idea that the c-Abl/p73 pathway is involved in 6-hydroxydopamine degeneration and suggest that inhibition of its kinase activity might be used as a therapeutical drug in Parkinson's disease.