Role of Abl1 kinase in axon initial segment disassembly and its consequences on axonal trafficking in Alzheimer’s disease.
| dc.catalogador | pau | |
| dc.contributor.advisor | Álvarez Rojas, Alejandra | |
| dc.contributor.author | Stuardo Castillo, Nicolás Gabriel | |
| dc.contributor.other | Pontificia Universidad Católica de Chile. Facultad de Ciencias Biológicas | |
| dc.date.accessioned | 2024-06-05T15:22:53Z | |
| dc.date.available | 2024-06-05T15:22:53Z | |
| dc.date.issued | 2024 | |
| dc.date.updated | 2024-06-03T14:37:16Z | |
| dc.description | Tesis (Doctor en Ciencias Biológicas con mención en Biología Celular y Molecular)--Pontificia Universidad Católica de Chile, 2024 | |
| dc.description.abstract | Axon initial segment disassembly has recently begun to be appreciated as an important event in Alzheimer’s disease pathology as it directly impacts neuronal compartmentalization, leading to pathological processes like tau missorting. However, the molecular mechanisms that underlie the collapse of the axon initial segment scaffold are incompletely understood. Our lab has previously shown that Abl1 kinase, a non-receptor tyrosine kinase with multiple functions, becomes aberrantly activated in Alzheimer’s disease and promotes multiple deleterious cellular processes including dendritic spine collapse, tau hyperphosphorylation, neuronal apoptosis, among others. Given the important role of Abl1 in Alzheimer’s disease pathology and its emerging role in tau pathology, we set out to evaluate whether it could participate directly in axon initial segment collapse. Our results show that inhibition of Abl1 prevents amyloid-β fibril–promoted axon initial segment collapse, and conversely, that Abl1 allosteric activation promotes loss of Ankyrin G clustering. Through cytosolic extraction experiments, we show that active Abl1 associates to the axon initial segment scaffold, and that this association increases in response to amyloid-β fibril treatment. Furthermore, through expansion microscopy experiments we show that Abl1 can be found in the axon initial segment in vivo and in vitro. We then evaluated the effects of Abl1 activation on the axon initial segment actin cytoskeleton and found that it promotes a decrease in actin patch area and a generalized decrease in phalloidin stain intensity. In order to further our understanding of the underlying molecular mechanism, we evaluated the participation of MICAL3, a known AIS actin patch depolymerizing protein and Abl1 interactor, in the process of actin patch loss. Interestingly, we find that Abl1 appears to recruit MICAL3 to actin patches and that silencing MICAL3 expression with a shRNA precludes the actin patch disassembly induced by Abl1 activation, shedding light on a possible mechanism of AIS actin cytoskeleton disruption by Abl1. Finally, we evaluated 2 different cargoes that have been previously shown to depend on axon initial segment integrity for its correct compartmentalization: Rab11, a somatodendritic protein, and tau, an axonal protein. Strikingly, we find that Rab11 missorts into the axon, and tau missorts into the somatodendritic compartment in response to Abl1 activation, demonstrating a bidirectional failure in AIS barrier function. Taken together, our results show that Abl1 plays an important role in AIS destabilization and that this has important consequences in terms of protein compartmentalization, which are relevant processes in Alzheimer’s disease pathology. | |
| dc.fechaingreso.objetodigital | 2024-06-05 | |
| dc.format.extent | xii, 97 páginas | |
| dc.fuente.origen | Autoarchivo | |
| dc.identifier.doi | 10.7764/tesisUC/BIO/86434 | |
| dc.identifier.uri | https://doi.org/10.7764/tesisUC/BIO/86434 | |
| dc.identifier.uri | https://repositorio.uc.cl/handle/11534/86434 | |
| dc.information.autoruc | Facultad de Ciencias Biológicas; Álvarez Rojas, Alejandra; 0000-0002-8129-9280; 83681 | |
| dc.information.autoruc | Facultad de Ciencias Biológicas; Stuardo Castillo, Nicolás Gabriel; S/I; 221037 | |
| dc.language.iso | en | |
| dc.nota.acceso | contenido completo | |
| dc.rights | acceso abierto | |
| dc.rights.license | Atribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0) | |
| dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es | |
| dc.subject.ddc | 570 | |
| dc.subject.dewey | Biología | es_ES |
| dc.subject.ods | 03 Good health and well-being | |
| dc.subject.odspa | 03 Salud y bienestar | |
| dc.title | Role of Abl1 kinase in axon initial segment disassembly and its consequences on axonal trafficking in Alzheimer’s disease. | |
| dc.type | tesis doctoral | |
| sipa.codpersvinculados | 83681 | |
| sipa.codpersvinculados | 221037 |