Publication: Modulación de TDP-43: una nueva estrategia terapéutica para la esclerosis lateral amiotrófica
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2021-07-15
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Universidad Complutense de Madrid
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Abstract
Los grandes avances en el campo de la medicina han contribuido al aumento de la esperanza de vida media de la población. Este hecho va ligado al incremento del número de casos de enfermedades neurodegenerativas siendo las más incidentes la enfermedad de Alzheimer y la enfermedad de Parkinson. La esclerosis lateral amiotrófica, conocida como ELA, es la enfermedad de neurona motora más frecuente en adultos. Aunque es una enfermedad rara, el aumento considerable del número de casos en los últimos años ha hecho que su visibilidad sea cada vez mayor. Esta patología se caracteriza por la pérdida progresiva de neuronas motoras que acaba derivando en una parálisis muscular de pronóstico mortal, siendo la esperanza de vida media desde el diagnostico de 3 a 4 años. La búsqueda de terapias efectivas que consigan frenar la degeneración neuronal de esta devastadora enfermedad es de gran necesidad puesto que los dos únicos fármacos aprobados son paliativos y tan solo son capaces de alargar la vida de los pacientes de 3 a 6 meses.
La ELA, al igual que la mayoría de patologías neurodegenerativas, es una enfermedad multifactorial, es decir, la muerte neuronal es consecuencia de la suma de diversos procesos celulares patológicamente alterados. Un biomarcador común a todas ellas, es la presencia de agregados proteicos citoplasmáticos en las células afectadas como consecuencia de modificaciones post-traduccionales anómalas que sufren en su estructura, como es la hiperfosforilación y la ubiquitinación. La característica patológica principal presente en los tejidos de un 97% de pacientes con ELA, es la agregación citoplasmática de TDP-43 fosforilada y ubiquitinada. TDP-43 regula la expresión de más de 600 ARNm a nivel nuclear, sin embargo, en estado patológico se trasloca al citoplasma y agrega produciéndose en consecuencia una desregulación de numerosos procesos celulares. De ahí la importancia que adquiere la búsqueda de fármacos que reestablezcan la homeostasis de esta proteína tan esencial.
Así, el desarrollo de inhibidores de las proteínas quinasas implicadas en la fosforilación de TDP-43, ha adquirido gran relevancia en la comunidad científica y en concreto en este grupo de investigación, cuya práctica en el desarrollo de inhibidores de quinasas para diferentes patologías, cuenta con más de 20 años de experiencia. Con esta intención, se ha desarrollado la presente Tesis Doctoral bajo el nombre: “Modulación de TDP-43: una nueva estrategia terapéutica para la esclerosis lateral amiotrófica”, en la que el principal objetivo ha sido la validación de las proteínas quinasas que modulan la fosforilación de TDP-43 como dianas terapéuticas, así como el desarrollo de sus inhibidores como candidatos a fármacos para la ELA y aquellas patologías que cursen con esta proteinopatía...
The prevalence of neurodegenerative diseases increases daily due to the longer life expectancy of the population as there are age-dependent diseases. The most common disorders by the number of patients are Alzheimer´s disease, Parkinson´s disease and in a lower range amyotrophic lateral sclerosis commonly known as ALS. ALS is a lethal motor neuron disease characterized by the progressive muscle paralysis due to the upper and lower motor neuron degeneration being the average survival from onset to death between 3-4 years. The unknown etiology and the lack of effective treatment highlighted the urgent need to discover effective disease-modifying targets and therefore effective treatments to prevent and stop disease progression. ALS is considered as a multifactorial disorder where a combination of environmental and genetic factors contributes to motorneuron degeneration. Protein aggregates with different posttranslational modifications such as hyperphosphorylation and ubiquitination, is one of the most common biomarkers among neurodegenerative diseases. The main pathological hallmark in almost 97% of ALS patients is the presence of TDP-43 protein aggregates in the cytoplasm of the affected cells promoted by the aberrant phosphorylation and other post-translational modifications. TDP-43 is a nuclear protein involved in the regulation of multiple cellular processes as it regulates the transcription and transport of more than 600 mRNA. The dynamic equilibrium of TDP-43 between nucleus and cytoplasm is altered in disease-affected neurons causing a dysregulation of several mechanisms. Therefore, the inhibition of protein kinases involved in the abnormal phosphorylation of TDP-43 has emerged as a promising therapeutic approach for ALS in order to recover TDP-43 homeostasis and therefore multiple signalling pathways. With this purpose, we have carried out a medicinal chemistry program where the thesis “TDP-43 modulation: a novel therapeutic approach for Amyotrophic Lateral Sclerosis” have taken place, whose the main goal has been the validation of protein kinases as new therapeutic targets and the develop of protein kinases inhibitors as valuable drugs to treat ALS and TDP-43 proteinopathy disorders...
The prevalence of neurodegenerative diseases increases daily due to the longer life expectancy of the population as there are age-dependent diseases. The most common disorders by the number of patients are Alzheimer´s disease, Parkinson´s disease and in a lower range amyotrophic lateral sclerosis commonly known as ALS. ALS is a lethal motor neuron disease characterized by the progressive muscle paralysis due to the upper and lower motor neuron degeneration being the average survival from onset to death between 3-4 years. The unknown etiology and the lack of effective treatment highlighted the urgent need to discover effective disease-modifying targets and therefore effective treatments to prevent and stop disease progression. ALS is considered as a multifactorial disorder where a combination of environmental and genetic factors contributes to motorneuron degeneration. Protein aggregates with different posttranslational modifications such as hyperphosphorylation and ubiquitination, is one of the most common biomarkers among neurodegenerative diseases. The main pathological hallmark in almost 97% of ALS patients is the presence of TDP-43 protein aggregates in the cytoplasm of the affected cells promoted by the aberrant phosphorylation and other post-translational modifications. TDP-43 is a nuclear protein involved in the regulation of multiple cellular processes as it regulates the transcription and transport of more than 600 mRNA. The dynamic equilibrium of TDP-43 between nucleus and cytoplasm is altered in disease-affected neurons causing a dysregulation of several mechanisms. Therefore, the inhibition of protein kinases involved in the abnormal phosphorylation of TDP-43 has emerged as a promising therapeutic approach for ALS in order to recover TDP-43 homeostasis and therefore multiple signalling pathways. With this purpose, we have carried out a medicinal chemistry program where the thesis “TDP-43 modulation: a novel therapeutic approach for Amyotrophic Lateral Sclerosis” have taken place, whose the main goal has been the validation of protein kinases as new therapeutic targets and the develop of protein kinases inhibitors as valuable drugs to treat ALS and TDP-43 proteinopathy disorders...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, leída el 07/05/2021