{"id":1298,"date":"2018-11-09T10:47:22","date_gmt":"2018-11-09T10:47:22","guid":{"rendered":"https:\/\/www.ull.es\/servicios\/otri\/?post_type=proyectos-nacionales&p=1298"},"modified":"2019-05-24T13:50:05","modified_gmt":"2019-05-24T13:50:05","slug":"d2rd3rautophagy","status":"publish","type":"proyectos-nacionales","link":"https:\/\/www.ull.es\/servicios\/otc\/fr\/proyectos\/proyectos-nacionales\/d2rd3rautophagy\/","title":{"rendered":"BFU2016-77363-R. R\u00e9gulation de l'autophagie par les agonistes dopaminergiques D2R\/D3R : induction ou inhibition, s\u00e9lectivit\u00e9 pour D2R ou D3R et neuroprotection."},"content":{"rendered":"

[vc_row][vc_column][vc_tta_accordion shape=\u00bbsquare\u00bb c_icon=\u00bbchevron\u00bb c_position=\u00bbright\u00bb active_section=\u00bb\u00bb no_fill=\u00bbtrue\u00bb collapsible_all=\u00bbtrue\u00bb][vc_tta_section title=\u00bbResumen\u00bb tab_id=\u00bbresumen\u00bb][vc_column_text]<\/p>\n

La disfunci\u00f3n de la autofagia juega un papel fundamental en la patogenia de las enfermedades neurodegenerativas (END) al provocar la formaci\u00f3n de agregados de prote\u00ednas mal plegadas que en su fase oligom\u00e9rica son citot\u00f3xicos causando la muerte neuronal. Por tanto, la inducci\u00f3n de autofagia, al prevenir la formaci\u00f3n de agregados proteicos, es una alternativa terap\u00e9utica prometedora en las END. Sin embargo, dependiendo del entorno celular, la autofagia puede causar tambi\u00e9n muerte celular. Este hecho tiene particular relevancia en las END ya que requieren tratamiento prolongado y los inductores de autofagia disponibles actualmente act\u00faan de forma no-selectiva en todas las c\u00e9lulas. Ser\u00eda interesante encontrar inductores de autofagia con un alto \u00edndice terap\u00e9utico (ratio dosis terap\u00e9utica\/dosis t\u00f3xica) y que act\u00faen de forma selectiva en poblaciones neuronales espec\u00edficas. Las neuronas dopamin\u00e9rgicas mesencef\u00e1licas y las medianas espinosas estriatales, dianas principales de la degeneraci\u00f3n en la enfermedad de Parkinson (EP) y enfermedad de Huntington (EH) respectivamente, expresan los receptores DA\u00e9rgicos D2 (D2R) y D3 (D3R). Estudios recientes indican que los ligandos D2R\/D3R modulan la autofagia, sin embargo los hallazgos en cuanto a su capacidad inductora o inhibitoria son contradictorios. Tras administraci\u00f3n de agonistas o antagonistas D2R\/D3R se ha descrito tanto inducci\u00f3n como inhibici\u00f3n\/disrupci\u00f3n de autofagia. Las discrepancias pueden deberse a diferencias tanto en las condiciones experimentales como en la interpretaci\u00f3n de los marcadores de autofagia. Datos de nuestro laboratorio utilizando pramipexol (PPX), un agonista dopamin\u00e9rgico D2R\/D3R D3R preferente, en modelos celulares y animales muestran que: 1. a bajas dosis, PPX induce autofagia por la ruta cl\u00e1sica (mTOR-dependiente) mediada por D3R, y 2. a dosis m\u00e1s altas, PPX induce cambios en marcadores de autofagia no mediados por D3R. Estos cambios pueden: a) corresponder tanto a activaci\u00f3n de autofagia por la ruta mTOR-independiente como a disregulaci\u00f3n (inhibici\u00f3n) de autofagia, b) ser mediados por D2R o por mecanismos no DA\u00e9rgicos, y c) tener un efecto protector o t\u00f3xico. Nuestra hip\u00f3tesis es que el efecto neuroprotector de los agonistas D2R\/D3R como inductores de autofagia depende de la selectividad D3R en su se\u00f1alizaci\u00f3n. Los agonistas D3R preferentes, administrados a dosis bajas (se\u00f1alizaci\u00f3n selectiva D3R), previenen la formaci\u00f3n de agregados proteicos por activaci\u00f3n de autofagia a trav\u00e9s de la v\u00eda cl\u00e1sica (mTOR-dependiente). A dosis m\u00e1s altas (no D3R selectivas), actuando bien a trav\u00e9s de D2R o de mecanismos no DA\u00e9rgicos, producen cambios en marcadores de autofagia que pueden estar relacionados con autofagia reactiva a da\u00f1o celular, disregulaci\u00f3n de autofagia y\/o activaci\u00f3n de apoptosis. El objetivo de este proyecto es:<\/p>\n

    \n
  1. Demostrar que los agonistas DA\u00e9rgicos D2R\/D3R inducen autofagia en neuronas DA\u00e9rgicas mesencef\u00e1licas y medianas espinosas estriatales a trav\u00e9s de D3R e inhibici\u00f3n de mTOR,<\/li>\n
  2. Demostrar que este efecto previene la formaci\u00f3n de agregados de a-sinucle\u00edna y huntingtina mutada en modelos animales de EP y EH, respectivamente y<\/li>\n
  3. Investigar si la se\u00f1alizaci\u00f3n no-D3R (D2R o no-DA\u00e9rgicos) de agonistas D2R\/D3R provoca autofagia mTOR- independiente, disrupci\u00f3n\/inhibici\u00f3n de autofagia y\/o da\u00f1o celular.<\/li>\n<\/ol>\n

    [\/vc_column_text][\/vc_tta_section][vc_tta_section title=\u00bbAbstract\u00bb tab_id=\u00bbabstract\u00bb][vc_column_text]<\/p>\n

    Autophagy dysfunction plays a central role in the pathogenesis of neurodegenerative diseases (NDD) by provoking the aggregation of misfolded proteins which are cytotoxic in their oligomeric form and lead to cell death. So, autophagy induction can prevent the formation of protein aggregates and is a promising therapy in NDD. However, depending on the cellular environment, autophagy can also promote cell death. This fact is particularly relevant in NDD because they require long-time treatment and autophagy inducers available nowadays are not selective for specific cell populations. It would be interesting to find autophagy inducers with a high therapeutic index (therapeutic dose\/toxic dose ratio) and which act selectively on specific neuronal populations. Midbrain dopaminergic (DAergic) neurons and striatal medium spiny neurons, the main target of degeneration in Parkinsons disease (PD) and Huntingtons disease (HD), respectively, express the DAergic D2 receptor (D2R) and D3 receptor (D3R). Recent reports show that autophagy can be regulated by D2R\/D3R ligands. However, the findings about their capacity as inducers or inhibitors are contradictory. Both induction and inhibition\/disruption have been described after agonist or antagonist administration. Discrepancies may be due to differences in experimental conditions as well as in the interpretation of autophagy markers. Our experiments using pramipexole (PPX), a D3R preferential D2R\/D3R agonist, in cell and animal models show that: 1. At low doses, PPX induces D3R-mediated classical (mTOR-dependent) autophagy, and 2: At high doses, PPX induces non D3R-mediated changes in autophagy markers. These changes may: a) reflect either activation of non-classical autophagy (mTOR-independent) or autophagy dysregulation\/inhibition, b) be mediated by D2R or by non-DAergic mechanisms, and c) have a protective or toxic effect. Our hypothesis is that the neuroprotective effect of D2R\/D3R agonists as autophagy inducers depends on their selectivity for D3R signaling. At low doses (D3R selective signaling), D3R preferential agonists prevent the formation of protein aggregates through the activation of classical (mTOR-dependent) autophagy. At high doses (D3R non- selective signaling), acting through either D2R or nonDAergic mechanisms, these agonists promote changes in autophagy markers that can be due to autophagy activation in response to cell damage, autophagy dysregulation or apoptosis activation. Our aim is:<\/p>\n

      \n
    1. To demonstrate that DAergic D2R\/D3R agonists induce autophagy in midbrain dopaminergic (DAergic) neurons and striatal medium spiny neurons through D3R signaling and mTOR inhibition,<\/li>\n
    2. To demonstrate that this effect prevents the formation of \u03b1- synuclein and mutant huntingtin aggregates in animal models of PD and HD, respectively, and<\/li>\n
    3. To investigate whether non-D3R (D2R or non-DAergic) signaling of D2R\/D3R agonsits promotes mTOR-independent autophagy, autophagy inhibition\/disruption and \/or cell damage.<\/li>\n<\/ol>\n

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