Characterization of the effect of Latrepirdine in models of alpha-synuclein overexpression

Scientific evidence suggests that the accumulation of α-synuclein (α-syn) protein could contribute to the formation of proteotoxics species, mitochondrial dysfunction and neurodegeneration observed in Parkinson's disease (PD) and other synucleinopathies. Although the exact mechanism of neurotox...

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Autor: Delgado Oyarzo, Luz Marina
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2017
País:Chile
OAI Identifier:oai:repositorio.anid.cl:10533/208861
Acceso en línea:https://hdl.handle.net/10533/208861
Access Level:acceso abierto
Palabra clave:Medicina y Ciencias de la Salud
Biotecnología Médica
Biología Celular
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dc.title.es_CL.fl_str_mv Characterization of the effect of Latrepirdine in models of alpha-synuclein overexpression
dc.title.none.fl_str_mv Characterizatión of the effect of latrepirdine in models of alpha-synuclein overexpressión
title Characterization of the effect of Latrepirdine in models of alpha-synuclein overexpression
spellingShingle Characterization of the effect of Latrepirdine in models of alpha-synuclein overexpression
Delgado Oyarzo, Luz Marina
Medicina y Ciencias de la Salud
Biotecnología Médica
Biología Celular
title_short Characterization of the effect of Latrepirdine in models of alpha-synuclein overexpression
title_full Characterization of the effect of Latrepirdine in models of alpha-synuclein overexpression
title_fullStr Characterization of the effect of Latrepirdine in models of alpha-synuclein overexpression
title_full_unstemmed Characterization of the effect of Latrepirdine in models of alpha-synuclein overexpression
title_sort Characterization of the effect of Latrepirdine in models of alpha-synuclein overexpression
dc.creator.none.fl_str_mv Delgado Oyarzo, Luz Marina
author Delgado Oyarzo, Luz Marina
author_facet Delgado Oyarzo, Luz Marina
author_role author
dc.contributor.advisor.none.fl_str_mv Bernales, Sebastian
Valenzuela, Pablo
Alfaro, Ivan
Tischler, Nicole
Perez-Acle, Tomas
dc.contributor.institution.es_CL.fl_str_mv UNIVERSIDAD ANDRES BELLO
dc.subject.oecd1n.es_CL.fl_str_mv Medicina y Ciencias de la Salud
topic Medicina y Ciencias de la Salud
Biotecnología Médica
Biología Celular
dc.subject.oecd2n.es_CL.fl_str_mv Biotecnología Médica
dc.subject.oecd3n.es_CL.fl_str_mv Biología Celular
description Scientific evidence suggests that the accumulation of α-synuclein (α-syn) protein could contribute to the formation of proteotoxics species, mitochondrial dysfunction and neurodegeneration observed in Parkinson's disease (PD) and other synucleinopathies. Although the exact mechanism of neurotoxicity and the identity of the toxic species of α-syn involved in neurodegeneration has not been clarified, recent research suggests that an increase in the concentration of α-syn, due to an increase in expression and / or due to the failure of mechanisms of proteostasis, promote the formation of soluble oligomers non-fibrillar of the protein, which would be responsible for synaptic dysfunction and neuronal degeneration observed in PD. The α-syn protein is degraded by the ubiquitin-proteasome system and autophagic-lysosomal pathway, which involves mechanisms of macroautophagy, microautophagy and selective chaperone-mediated autophagy (CMA). Increased levels of α-syn and deficiencies in the activity of these protein degradation systems have been detected in brain and tissue of sporadic PD patients suggesting that a deficiency in the proteostasis of α-syn might be relevant in the development of disease. Current treatments for PD and other synucleinopathies are only symptomatic, and there are no therapeutic strategies that have proven to slow the neurodegenerative process. In this context, it has been suggested that the control of the concentration of α-syn, by inhibiting its synthesis or increased degradation, could be an important therapeutic strategy in decreasing the progression of dysfunction and neuronal death, besides contributing delay symptomatic progression of disease. A study during this work show that Latrepirdine, a molecule of the beta-carbolines family, reduce cytotoxicity by overexpression induced α-syn in neuronal cell line SH-SY5Y and is able to decrease the overall levels protein. Furthermore, it was found that the decrease in α-syn induced by Latrepirdine is mediated by a post-translational dependent lysosomal activity mechanism and Latrepirdine induce the selective activation of AMC at nanomolar concentrations, this being the first report of a molecule that activates the AMC.
publishDate 2017
dc.date.issued.es_CL.fl_str_mv 2017
dc.date.accessioned.none.fl_str_mv 2018-03-12T13:07:29Z
2022-08-22T20:20:55Z
dc.date.available.none.fl_str_mv 2018-03-12T13:07:29Z
2022-08-22T20:20:55Z
dc.type.none.fl_str_mv Tesis Doctorado
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dc.identifier.uri.none.fl_str_mv https://hdl.handle.net/10533/208861
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spelling UNIVERSIDAD ANDRES BELLODelgado Oyarzo, Luz Marina2017https://hdl.handle.net/10533/208861http://purl.org/coar/access_right/c_abf2Biología CelularBiotecnología MédicaMedicina y Ciencias de la SaludCharacterization of the effect of Latrepirdine in models of alpha-synuclein overexpressionBernales, SebastianValenzuela, PabloAlfaro, IvanTischler, NicolePerez-Acle, TomasUNIVERSIDAD ANDRES BELLOChileDelgado Oyarzo, Luz Marina2018-03-12T13:07:29Z2022-08-22T20:20:55Z2018-03-12T13:07:29Z2022-08-22T20:20:55Z2017Scientific evidence suggests that the accumulation of α-synuclein (α-syn) protein could contribute to the formation of proteotoxics species, mitochondrial dysfunction and neurodegeneration observed in Parkinson's disease (PD) and other synucleinopathies. Although the exact mechanism of neurotoxicity and the identity of the toxic species of α-syn involved in neurodegeneration has not been clarified, recent research suggests that an increase in the concentration of α-syn, due to an increase in expression and / or due to the failure of mechanisms of proteostasis, promote the formation of soluble oligomers non-fibrillar of the protein, which would be responsible for synaptic dysfunction and neuronal degeneration observed in PD. The α-syn protein is degraded by the ubiquitin-proteasome system and autophagic-lysosomal pathway, which involves mechanisms of macroautophagy, microautophagy and selective chaperone-mediated autophagy (CMA). Increased levels of α-syn and deficiencies in the activity of these protein degradation systems have been detected in brain and tissue of sporadic PD patients suggesting that a deficiency in the proteostasis of α-syn might be relevant in the development of disease. Current treatments for PD and other synucleinopathies are only symptomatic, and there are no therapeutic strategies that have proven to slow the neurodegenerative process. In this context, it has been suggested that the control of the concentration of α-syn, by inhibiting its synthesis or increased degradation, could be an important therapeutic strategy in decreasing the progression of dysfunction and neuronal death, besides contributing delay symptomatic progression of disease. A study during this work show that Latrepirdine, a molecule of the beta-carbolines family, reduce cytotoxicity by overexpression induced α-syn in neuronal cell line SH-SY5Y and is able to decrease the overall levels protein. Furthermore, it was found that the decrease in α-syn induced by Latrepirdine is mediated by a post-translational dependent lysosomal activity mechanism and Latrepirdine induce the selective activation of AMC at nanomolar concentrations, this being the first report of a molecule that activates the AMC.Existe evidencia que sugiere que la acumulación de la proteína α-sinucleína (α-syn) podría contribuir a la formación de especies proteotóxicas, a la disfunción mitocondrial y a la neurodegeneración observadas en la enfermedad de Parkinson (EP) y en otras sinucleopatías. Aunque el mecanismo exacto de neurotoxicidad y la identidad de las especies toxicas de α-syn que participan en la neurodegeneración no ha sido clarificado, investigaciones recientes apuntan a que un aumento en la concentración de α-syn, producto de un aumento en su expresión y/o debido a la falla de sus mecanismos de proteostasis, promovería la formación de oligómeros solubles no fibrilares de la proteína, los cuales serían los responsables de la disfunción sináptica y de la degeneración neuronal observada en la EP. La proteína α-syn es degradada por el sistema proteosoma-ubiquitina y por la vía autofágica-lisosomal, la cual involucra los mecanismos de macroautofagia, microautofagia y la autofagia selectiva mediada por chaperona (AMC). Niveles aumentados de α-syn y deficiencias en la actividad de estos sistemas de degradación de proteínas han sido detectados en cerebros y tejidos de pacientes con EP esporádico lo que sugiere que una deficiencia en la proteostasis de α-syn podría ser relevante en el desarrollo de la enfermedad. Los tratamientos actuales para la EP y para otras sinucleopatías son únicamente sintomáticos, y no existen estrategias terapéuticas que hayan demostrado retardar el proceso neurodegenerativo. En este contexto, se ha sugerido que el control de la concentración de α-syn, mediante la inhibición de su síntesis o el aumento de su degradación, podría ser una estrategia terapéutica importante en la disminución de la progresión de la disfunción y muerte neuronal, además de contribuir en retardar la progresión sintomática de la enfermedad. Los estudios realizados durante este trabajo demuestran que Latrepirdina, una molécula de la familia de los beta-carbolinos, reduce la citotoxicidad inducida por la sobreexpresión de α-syn en la línea celular neuronal SH-SY5Y y es capaz de disminuir los niveles totales de la proteína. Además, se encontró que la disminución de α-syn inducida por Latrepirdina, es mediada por un mecanismo post-traduccional dependiente de la actividad lisosomal y que Latrepirdina induce la activación selectiva de la AMC a concentraciones nanomolares, siendo este el primer reporte de una molécula que activa la AMC.PFCHA-BecasPFCHA-Becas21100563https://hdl.handle.net/10533/208861instname: Conicytreponame: Repositorio Digital RI2.0info:eu-repo/grantAgreement//21100563info:eu-repo/semantics/dataset/hdl.handle.net/10533/93488info:eu-repo/semantics/openAccessCC0 1.0 Universalhttp://creativecommons.org/publicdomain/zero/1.0/Medicina y Ciencias de la SaludBiotecnología MédicaBiología CelularCharacterization of the effect of Latrepirdine in models of alpha-synuclein overexpressionCharacterizatión of the effect of latrepirdine in models of alpha-synuclein overexpressiónTesis Doctoradoinfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionTesisTesishttps://hdl.handle.net/10533/208861PFCHA-Becas2d99d1cf-bdcc-4d6a-bbf0-653d4357c9c6virtual::63401-12d99d1cf-bdcc-4d6a-bbf0-653d4357c9c6virtual::63401-1ORIGINALTesis Luz Delgado .pdfapplication/pdf2769856https://repositorio.anid.cl/bitstreams/15fa9f2b-3ddf-41b0-9337-4ceb547028ed/downloadebc7d8013d8839e515f7c06c3fc467cfMD51CC-LICENSElicense_rdfapplication/octet-stream1089https://repositorio.anid.cl/bitstreams/1c3b4f8e-baa3-490c-9261-d76d2fd18879/download0a703d871bf062c5fdc7850b1496693bMD52LICENSElicense.txttext/plain1779https://repositorio.anid.cl/bitstreams/91e2049c-697f-4105-88ef-29d8083dab7e/download593a6e7305c66c56041a9f9e15a649c1MD53TEXTTesis Luz Delgado .pdf.txtExtracted texttext/plain159533https://repositorio.anid.cl/bitstreams/1d6cea36-9a27-4670-b312-a68da7641447/download21c2c0521b263504bae5175ed902f002MD54THUMBNAILTesis Luz Delgado .pdf.jpgIM Thumbnailimage/jpeg2209https://repositorio.anid.cl/bitstreams/cb2e21dc-5683-4512-80cb-1165b3f46b7a/download4afbcf4eb25d6d12727043f057b3baecMD5510533/208861oai:repositorio.anid.cl:10533/2088612023-07-24 06:29:02.218http://creativecommons.org/publicdomain/zero/1.0/info:eu-repo/semantics/openAccesshttps://repositorio.anid.clRepositorio ANIDaletelier@anid.clTGljZW5jaWEgZGUgRGlzdHJpYnVjacOzbiBObyBFeGNsdXNpdmEKCkFsIGZpcm1hciB5IHByZXNlbnRhciBlc3RhIGxpY2VuY2lhICwgdXN0ZWQgKGVsIGF1dG9yKGVzKSBvIHRpdHVsYXIgZGUgZGVyZWNob3MgZGUgYXV0b3IpIGdhcmFudGl6YSBhIGxhIENvbWlzacOzbiBOYWNpb25hbCBkZSBJbnZlc3RpZ2FjacOzbiBDaWVudMOtdGljYSB5IFRlY25vbMOzZ2ljYSAoQ09OSUNZVCkgZWwgZGVyZWNobyBubyBleGNsdXNpdm8gZGUgcmVwcm9kdWNpciAsIHRyYWR1Y2lyIChjb21vIHNlIGRlZmluZSBtw6FzIGFiYWpvKSAsIHkvbyBkaXN0cmlidWlyIHN1IGRvY3VtZW50byAoaW5jbHV5ZW5kbyBlbCByZXN1bWVuKSBlbiB0b2RvIGVsIG11bmRvIGVuIGZvcm1hIGltcHJlc2EgeSBlbiBmb3JtYXRvIGVsZWN0csOzbmljbyB5IGVuIGN1YWxxdWllciBtZWRpbywgaW5jbHV5ZW5kbywgcGVybyBubyBsaW1pdGFkbyBhLCBhdWRpbyBvIHbDrWRlby4KClVzdGVkIGFjZXB0YSBxdWUgQ09OSUNZVCBwdWVkZSwgc2luIGFsdGVyYXIgc3UgY29udGVuaWRvLCBjb252ZXJ0aXJsbyBhIGN1YWxxdWllciBtZWRpbyBvIGZvcm1hdG8gcGFyYSBlbCBmaW4gZGUgbGEgY29uc2VydmFjacOzbi4KClRhbWJpw6luIGFjZXB0YSBxdWUgQ09OSUNZVCBwdWVkZSB0ZW5lciBtw6FzIGRlIHVuYSBjb3BpYSBkZSBlc3RlIGRvY3VtZW50byBwYXJhIGZpbmVzIGRlIHNlZ3VyaWRhZCwgY29waWFzIGRlIHNlZ3VyaWRhZCB5IGNvbnNlcnZhY2nDs24uCgpVc3RlZCBkZWNsYXJhIHF1ZSBlbCBkb2N1bWVudG8gZXMgdW4gdHJhYmFqbyBvcmlnaW5hbCwgeSBxdWUgdXN0ZWQgdGllbmUgZWwgZGVyZWNobyBkZSBvdG9yZ2FyIGxvcyBkZXJlY2hvcyBjb250ZW5pZG9zIGVuIGVzdGEgbGljZW5jaWEuIFRhbWJpw6luIGRlY2xhcmEgcXVlIHN1IHBldGljacOzbiBubywgYSBsbyBtZWpvciBkZSBzdSBjb25vY2ltaWVudG8sIGluZnJpbmdlIGxvcyBkZXJlY2hvcyBkZSBhdXRvciBkZSBuYWRpZS4KClNpIGVsIGRvY3VtZW50byBjb250aWVuZSBtYXRlcmlhbGVzIGRlIGxvcyBxdWUgbm8gdGllbmVuIGRlcmVjaG9zIGRlIGF1dG9yICwgdXN0ZWQgZGVjbGFyYSBxdWUgaGEgb2J0ZW5pZG8gZWwgcGVybWlzbyBzaW4gcmVzdHJpY2Npw7NuIGRlbCBwcm9waWV0YXJpbyBkZSBsb3MgZGVyZWNob3MgcmVxdWVyaWRvcyBwb3IgZXN0YSBsaWNlbmNpYSB5IHF1ZSBlc2UgbWF0ZXJpYWwgY3V5b3MgZGVyZWNob3Mgc29uIGRlIHRlcmNlcm9zIGVzdMOhIGNsYXJhbWVudGUgaWRlbnRpZmljYWRvIHkgcmVjb25vY2lkbyBlbiBlbCB0ZXh0byBvIGNvbnRlbmlkbyBkZWwgZG9jdW1lbnRvIGVudHJlZ2Fkby4KClNJIEVMIEVOVsONTyBTRSBCQVNBIEVOIEVMIFRSQUJBSk8gUVVFIEhBIFNJRE8gUEFUUk9OQURPIE8gQVBPWUFETyBQT1IgQUxHVU5BIElOU1RJVFVDScOTTiBRVUUgTk8gU0VBIENPTklDWVQsIFVTVEVEIEFDRVBUQSBRVUUgSEEgQ1VNUExJRE8gQSBDVUFMUVVJRVIgREVSRUNITyBERSBSRVZJU0nDk04gVSBPVFJBUyBPQkxJR0FDSU9ORVMgUkVRVUVSSURBUyBQT1IgRElDSE8gQ09OVFJBVE8gTyBBQ1VFUkRPLgoKQ09OSUNZVCBpZGVudGlmaWNhcsOhIGNsYXJhbWVudGUgc3Ugbm9tYnJlKGVzKSBjb21vIGVsIGF1dG9yKGVzKSBvIHByb3BpZXRhcmlvKHMpIGRlIGxhIHByZXNlbnRhY2nDs24gLCB5IG5vIGhhcsOhIG5pbmd1bmEgYWx0ZXJhY2nDs24sIGV4Y2VwdG8gc2Vnw7puIGxvIHBlcm1pdGlkbyBwb3IgbGEgbGljZW5jaWEsIHBhcmEgc3UgcHJlc2VudGFjacOzbi4K
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