C-ABL kinase in Niemann Pick type a disease : its implication in the pathogenic mechanisms leading to autophagic flux alterations and neurodegeneration.
| dc.contributor.advisor | Zanlungo Matsuhiro, Silvana | |
| dc.contributor.author | Marín Marín, Tamara Alejandra | |
| dc.contributor.other | Pontificia Universidad Católica de Chile. Facultad de Medicina | |
| dc.date.accessioned | 2020-04-24T14:38:01Z | |
| dc.date.available | 2020-04-24T14:38:01Z | |
| dc.date.issued | 2020 | |
| dc.description | Tesis (Doctor en Ciencias Médicas)--Pontificia Universidad Católica de Chile, 2020 | |
| dc.description.abstract | Niemann-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. | |
| dc.format.extent | 108 páginas | |
| dc.identifier.doi | 10.7764/tesisUC/MED/28699 | |
| dc.identifier.uri | https://doi.org/10.7764/tesisUC/MED/28699 | |
| dc.identifier.uri | https://repositorio.uc.cl/handle/11534/28699 | |
| dc.language.iso | en | |
| dc.nota.acceso | Contenido completo | |
| dc.rights | acceso abierto | |
| dc.subject.ddc | 616.3997 | |
| dc.subject.dewey | Medicina y salud | es_ES |
| dc.subject.other | Enfermedades de Niemann-Pick - Genética | es_ES |
| dc.subject.other | Proteínas tirosina quinasas | es_ES |
| dc.title | C-ABL kinase in Niemann Pick type a disease : its implication in the pathogenic mechanisms leading to autophagic flux alterations and neurodegeneration. | es_ES |
| dc.type | tesis doctoral | |
| sipa.codpersvinculados | 72650 | |
| sipa.codpersvinculados | 249923 |