Publication: Hacia una terapia neuroprotectora con cannabinoides en la enfermedad de Huntington : estudios preclínicos y clínicos
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2018-01-08
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Universidad Complutense de Madrid
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Abstract
La enfermedad de Huntington (EH) es una enfermedad con herencia autosómica dominante causada por una mutación en el gen IT15, que codifica la proteína huntingtina (HTT). Esta proteína presenta una amplia expresión células de mamíferos y, aunque su función exacta no es totalmente conocida, se sabe que está relacionada con la modulación de procesos celulares tales como transcripción génica, señalización celular, metabolismo energético y neurogénesis. La mutación consiste en una expansión excesiva del tracto de poliglutamina localizado en el extremo N-terminal de la proteína, lo cual afecta a su plegamiento y actividad normales, y lleva a la alteración de una serie de procesos celulares y la aparición de eventos citotóxicos (ej. Formación de agregados de la huntingtina mutada (mHTT), desregulación transcripcional, reducción de los niveles de BDNF, excitotoxicidad, alteraciones en la función mitocondrial, alteraciones en la degradación proteica y autofagia, estrés oxidativo, activación glial y respuesta inflamatoria). Todos estos eventos son causados bien por pérdida o por ganandia de función de la mHTT, la cual resulta ser tóxica y provocar la degeneración de subpoblaciones neuronales específicas localizadas en los ganglios basales, especialmente las neuronas medianas espinosas, y también en la corteza cerebral (neuronas piramidales). Además, en fases avanzadas de la enfermedad otras regiones cerebrales se ven también afectadas, tales como la substantia nigra, el tálamo y el hipocampo. Dependiendo de la longitud de la cola de poliglutamina, losprimeros síntomas aparecen generalmente como problemas cognitivos y psiquiátricos, al os que les siguen los trastornos motores característicos, los cuales tienen dos componentes principales: en primer lugar movimientos involuntarios o corea, los cuales comienzan temprano en el transcurso de la enfermedad; y en segundo lugar la incapacidad para realizar movimientos voluntarios, que incluye bradicinesia y falta de coordinación. Los trastornos mentales acaban llevando a demencia en fases avanzadas, y los síntomas se desarrollan inexorablemente hasta el desenlace fatal de la enfermedad, generalmente 15-20 años después de la aparición de los síntomas motores. Actualmente no existe ningún tratamiento efectivo para la EH, y los pocos tratamientos aprobados están centrados en el control de los síntomas. No existen aún terapias efectivas dirigidas a retrasar o detener el proceso degenerativo. Por este motivo, muchos compuestos centrados en la prevención o reducción del daño cerebral en pacientes de EH están ahora en investigación...
Huntington’s disease is an inherited autosomal dominant disease caused by a mutation in the IT15 gene that encodes the protein huntingtin (HTT). This protein is widely expressed in mammalian cells and, although its exact function still remains unclear, it appears to be related to the modulation cell processes such as gene transcription, cell signaling, energy metabolism and neurogenesis. The mutation consists in an excessive expansion of the polyglutamine tract of the protein located in its N-terminal domain, which alters protein folding and activity and leads to the disturbance of many cellular processes and the appearance of many cytotoxic events (e.g. aggregation of mutant HTT (mHTT), transcriptional dysregulation, reduced BDNF levels, excitotoxicity, altered mitochondrial function, alterations in protein degradation and autophagy, oxidative stress, glial activation and inflammatory responses). All these events are caused by either loss-of-function or gain-of-function in mHTT, which results to be toxic and elicit the degeneration of selective neuronal subpopulations in the basal ganglia, specifically the medium spiny neurons (MSNs), and also in the cerebral cortex (pyramidal cells). In addition, in advanced phases of the disease, other brain regions are also affected, such as substantia nigra, thalamus and hippocampus. Depending on the length of the poliglitamine tract, its earliest symptoms often appear as cognitive and neuropsychiatric issues and are followed by characteristic motor disorders, which have two major components: firstly involuntary movements or chorea, beginning early in course of the pathology; and second the impairment of voluntary movements, which include bradykinesia and lack of coordination. Signs and symptoms develop inexorably, leading mental issues generally to decline into dementia, until the fatal outcome of the disease, generally around 20 years after the appearance of motor impairment. To date, there is no effective treatment to cure HD, and the very few treatments approved are focused on ameliorating the symptoms. No effective therapies designed to delay or stop the neurodegenerative process are available yet. Therefore, there is an unmet need for neuroprotective strategies aimed at preventing or reducing brain damage in HD patients, and several agents are currently under research...
Huntington’s disease is an inherited autosomal dominant disease caused by a mutation in the IT15 gene that encodes the protein huntingtin (HTT). This protein is widely expressed in mammalian cells and, although its exact function still remains unclear, it appears to be related to the modulation cell processes such as gene transcription, cell signaling, energy metabolism and neurogenesis. The mutation consists in an excessive expansion of the polyglutamine tract of the protein located in its N-terminal domain, which alters protein folding and activity and leads to the disturbance of many cellular processes and the appearance of many cytotoxic events (e.g. aggregation of mutant HTT (mHTT), transcriptional dysregulation, reduced BDNF levels, excitotoxicity, altered mitochondrial function, alterations in protein degradation and autophagy, oxidative stress, glial activation and inflammatory responses). All these events are caused by either loss-of-function or gain-of-function in mHTT, which results to be toxic and elicit the degeneration of selective neuronal subpopulations in the basal ganglia, specifically the medium spiny neurons (MSNs), and also in the cerebral cortex (pyramidal cells). In addition, in advanced phases of the disease, other brain regions are also affected, such as substantia nigra, thalamus and hippocampus. Depending on the length of the poliglitamine tract, its earliest symptoms often appear as cognitive and neuropsychiatric issues and are followed by characteristic motor disorders, which have two major components: firstly involuntary movements or chorea, beginning early in course of the pathology; and second the impairment of voluntary movements, which include bradykinesia and lack of coordination. Signs and symptoms develop inexorably, leading mental issues generally to decline into dementia, until the fatal outcome of the disease, generally around 20 years after the appearance of motor impairment. To date, there is no effective treatment to cure HD, and the very few treatments approved are focused on ameliorating the symptoms. No effective therapies designed to delay or stop the neurodegenerative process are available yet. Therefore, there is an unmet need for neuroprotective strategies aimed at preventing or reducing brain damage in HD patients, and several agents are currently under research...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Bioquímica y Biología Molecular III, leída el 09-06-2017