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1.Intro Corregida Heterómeros de receptores de dopamina como dianas terapéuticas en la enfermedad de Parkinson y en discinesias inducidas por el tratamiento con L-DOPA Daniel Farré Pérez ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tdx.cat) i a través del Dipòsit Digital de la UB (diposit.ub.edu) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX ni al Dipòsit Digital de la UB. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX o al Dipòsit Digital de la UB (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora. ADVERTENCIA. La consulta de esta tesis queda condicionada a la aceptación de las siguientes condiciones de uso: La difusión de esta tesis por medio del servicio TDR (www.tdx.cat) y a través del Repositorio Digital de la UB (diposit.ub.edu) ha sido autorizada por los titulares de los derechos de propiedad intelectual únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con finalidades de lucro ni su difusión y puesta a disposición desde un sitio ajeno al servicio TDR o al Repositorio Digital de la UB. No se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR o al Repositorio Digital de la UB (framing). Esta reserva de derechos afecta tanto al resumen de presentación de la tesis como a sus contenidos. En la utilización o cita de partes de la tesis es obligado indicar el nombre de la persona autora. WARNING. On having consulted this thesis you’re accepting the following use conditions: Spreading this thesis by the TDX (www.tdx.cat) service and by the UB Digital Repository (diposit.ub.edu) has been authorized by the titular of the intellectual property rights only for private uses placed in investigation and teaching activities. Reproduction with lucrative aims is not authorized nor its spreading and availability from a site foreign to the TDX service or to the UB Digital Repository. Introducing its content in a window or frame foreign to the TDX service or to the UB Digital Repository is not authorized (framing). Those rights affect to the presentation summary of the thesis as well as to its contents. In the using or citation of parts of the thesis it’s obliged to indicate the name of the author. HETERÓMEROS DE RECEPTORES DE DOPAMINA COMO DIANAS TERAPÉUTICAS EN LA ENFERMEDAD DE PARKINSON Y EN DISCINESIAS INDUCIDAS POR EL TRATAMIENTO CON L-DOPA DOPA - TRATAMIENTO CON L TRATAMIENTO ENFERMEDAD DE PARKINSON Y EN DISCINESIASY INDUCIDAS POR EL ENFERMEDAD DE PARKINSON HETERÓMEROS DE RECEPTORES DE DOPAMINA COMO DIANAS TERAPÉUTICAS HETERÓMEROSEN LA DE RECEPTORES DE DOPAMINA sis sis Te Doctoral Daniel Farré Pérez Pérez Farré TESIS DOCTORAL 2014 Daniel Daniel Portada: Modificado de J.-L. Lanciego y A. Vazquez (2012). Montaje gentileza de J.- L. Lanciego. Tinción con técnica de acetilcolinesterasa de un corte parasagital del cerebro del primate Macaca fascicularis UNIVERSIDAD DE BARCELONA FACULTAD DE BIOLOGÍA DEPARTAMENTO DE BIOQUÍMICA Y BIOLOGÍA MOLECULAR HETERÓMEROS DE RECEPTORES DE DOPAMINA COMO DIANAS TERAPÉUTICAS EN LA ENFERMEDAD DE PARKINSON Y EN DISCINESIAS INDUCIDAS POR EL TRATAMIENTO CON L-DOPA Memoria presentada por el Licenciado en Biología DANIEL FARRÉ PÉREZ para optar al grado de Doctor por la Universidad de Barcelona Esta tesis se ha inscrito dentro del programa de doctorado de Biomedicina . El trabajo experimental y la redacción de la presente memoria han sido realizados en el Departamento de Bioquímica y Biología Molecular de la Facultad de Biología (Universidad de Barcelona) por Daniel Farré Pérez bajo la dirección del Dr. Rafael Franco Fernández y el Dr. Vicent Casadó Burillo Barcelona, Septiembre de 2014 Dr. Rafael Franco Fernández Dr. Vicent Casadó Burillo Daniel Farré Pérez A mis padres, Salva y Manoli, a mi hermana Ariadna, y a mis abuelas, Magdalena y Ana Con esta Tesis se cierra un capítulo de mi vida que abrí un caluroso día de Junio de 2009 enviando un correo electrónico a Rafa Franco para realizar unas prácticas de verano, y que ha continuado a lo largo de 5 años dando lugar a esta Tesis, en 2014. No sólo agradecer a los que menciono aquí sino a todos los que me han ayudado en algún momento de esta etapa, aún con gestos insignificantes, a hacer más agradable este camino. Primero de todo agradecer a los jefes de NBM por haberme ayudado aportando cada uno su granito de arena a mi Tesis y facilitarme el día a día en el laboratorio: gracias a Rafa por ser el primero en aceptarme en el grupo, por concederme la oportunidad de tener la beca, por permitirme hacer la estancia donde yo quisiera y por apostar tan fuerte con el tema D1-D3, entre otros; gracias a Vicent por su enorme comprensión en todos mis problemas, por estar dispuesto siempre a ayudar y resolver cualquier duda (y siempre con una sonrisa y un entra al meu despatx dejando de lado todo), por su gran conocimiento sobre la técnica estrella del binding y por muchas otras cosas; a Antoni por su gran meticulosidad, por su gran trabajo con el ADA, por sus correcciones tan exhaustivas de mis trabajos que sólo él sabe hacer, por ese “Bon dia” sonriente que siempre dice al entrar por la puerta y por mucho más; a Vicent y Antoni, agradecerlos conjuntamente por darme la oportunidad de permitir llevar experimentalmente el TFG de Júlia; a Carme por su enorme background de ciencia que no se le escapa nada y que tanto ha beneficiado al grupo en los proyectos; a Pepi por sus ideas en los seminarios de grupo, por convertirnos en científicos eficientes y por mover cielo y tierra para lograr tener los productos necesarios para nuestros experimentos; a Enric por saber liderar y unir diplomáticamente este gran proyecto/familia que es NBM y a Peter por su contribución al conocimiento de nuevas técnicas. También agradecer a J.-L. Lanciego y a su equipo del CIMA de Pamplona por abrirme las puertas de su laboratorio y dejarme trabajar con uno de los modelos más apasionantes del Parkinson. Gracias a J.-L. Labandeira y Ana M. Muñoz, de la Universidad de Santiago de Compostela, por el enorme trabajo con las ratas. Gracias a los investigadores post-doctorales: a Estefanía o Fifa, por su ayuda incondicional en todos los experimentos siempre con buena cara, por ser una genial compañera de prácticas de Lab II, de laboratorio y de congresos (no de coffee breaks por desgracia) y por su gran trabajo con los programas de imagen que ha salvado más de un paper y que pocos valoran; también no gracias por hacerme un poco más estéril de lo que soy, al usar ese estufa… A Gemma gracias por tu paciencia conmigo, por toda que no es poca de ayuda recibida (tanto verbal como en forma de cDNAs), por incluirme en tu artículo, y por haber levantado mi estado de ánimo cuando estaba bajo con nuestros debates entre casados/solteros, sexo-infidelidad/chicas y muchos otros. Ah y todo un detalle incluirme en los agradecimientos de tu Tesis aún conociéndonos poco. A David M. por su gran rigor científico, por sus propuestas hacia donde llevar los experimentos y por esos seminarios excelentes que hacías y que tanto me ha servido. Gracias a los compañeros/ doctorandos : a Jasmina por la bata prestada el primer día que vine de prácticas al grupo, por el incontable número de ayudas y favores recibidos y que me han salvado la vida en muchas ocasiones, por las vueltas a casa con Renfe debatiendo o rajando, por portarte conmigo tan bien especialmente al principio intentando que me integrara rápidamente con todos e invitándome a muchas cosas cuando no cobraba (por eso sí que te debo mil eurus ) y por muchas más cosas. A Lucía (ya lo dicen, más vale una maña que fuerza) por su gran conocimiento sobre cannabinoides y por resolverme muchas dudas que otros nunca tenían tiempo para resolver. A Edu por la inmensa paciencia, por dejarme heredar su gran y genial trabajo sobre el ADA y su poyata, y por haberme irradiado inconscientemente con viales que tenía escondidos bajo la poyata y contribuir junto a Estefanía, a no poder tener retoños en el futuro (aunque sí tuvimos Edu y yo retoños vía telefónica). Al dúo inmunogénico, Isaac Newton y Victor , por sus coffee breaks , por sus grandes momentos de humor (en ocasiones equivalentes a los momentos de humor muy malo y fácil), por el incansable deseo de hablar de gineceus y por sus divertidas salidas nocturnas en antros de mala muerte (acéptalo Isaac, jamás iremos a la sala Inferno). A Marc (“Stereo love es un temaaaazooo”) y Jana Bar-kesova (cerveceros desde 2011), porque gracias a que propusieron a Rafa coger a alguien en prácticas, mi Tesis no hubiera sido posible; también gracias a enseñarme todo acerca de los clones y demás técnicas en mis inicios. A Jana por tratarme siempre como uno más aunque fuera un ignorante de la ciencia, por el viaje a Praga, por las cervezas tomadas en bares de dudosa reputación y por los consejos; también un no gracias por no entender nunca mis temazos (Barbra streisand inside) y por grabar vídeos en el Lab difundidos sin permiso en las Tesis.
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