Edición epigenética del promotor de PSD95 como estrategia para el tratamiento de los síntomas de la Enfermedad de Huntington
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Fecha
2023
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Idioma
es
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Universidad Andrés Bello
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Licencia CC
Licencia CC
Resumen
La enfermedad de Huntington (HD) es una patología hereditaria, incurable y que se
produce por un aumento de los repetidos CAG en el exón 1 del gen de la proteína
Huntingtina. Esta patología se asocia con una serie de síntomas motores, que implican
un aumento en los movimientos involuntarios junto con otros síntomas
neuropatológicos. La fisiopatología de esta enfermedad se asocia con una serie de
eventos que ocurren de forma secuencial y cuyo origen se ha trazado hasta los
circuitos cortico-estriatales, desde donde se expande a otras regiones del cerebro,
particularmente hipocampo. A nivel celular, se han observado una serie de cambios
en la estructura de las sinapsis, los que tiene importantes consecuencias para el
establecimiento, mantención de los circuitos neuronales y para la sobrevida de la
neurona. Una de las proteínas asociadas a estas fallas es la proteína de la densidad
postsináptica 95 (PSD95) la que es abundante en las densidades postinápticas,
cumple funciones de andamiaje y que presenta una importante disminución en
pacientes de HD, asociandose con problemas cognitivos, motores y conductuales.
Nuestro laboratorio ha desarrollado una herramienta de edición epigenética conocida
como PSD95-6ZF-VP64, que se une a la región promotora del gen de PSD95,
promoviendo su expresión, restableciendo la transmisión sináptica y la densidad de
espinas dendríticas en neuronas hipocampales de un modelo de la enfermedad de
Alzheimer. En el presente trabajo se muestra que el animal R6/2, que presenta los
principales síntomas de HD en una ventana corta de tiempo, presenta niveles bajos de
mRNA y proteína de PSD95, los que pueden ser revertidos al tratar los animales con
PSD95-6ZF-VP64 luego de nacer. Este tratamiento además retrasa los síntomas
tempranos asociados a memoria y aprendizaje, característicos de la enfermedad, pero
no revierte la aparición de los síntomas tardíos. Esta evidencia sugiere que PSD95
estaría jugando un rol importante en las primeras fases de la patología, una de las
fases más largas y complejas para los pacientes y sus familias, lo que podría constituir
un atrayente blanco terapéutico para el tratamiento de la fase prodrómica de la
enfermedad.
Huntington's disease (HD) is an incurable hereditary pathology caused by an increase in the CAG repeats in exon 1 of the Huntingtin gene. This pathology is associated with a series of motor symptoms, involving an increase in involuntary movements, along with other neuropathological symptoms. The pathophysiology of this disease is associated with a series of events that occur sequentially and whose origin has been traced to the cortico-striatal circuits, from where it spreads to other regions of the brain, particularly the hippocampus. At the cellular level, a series of changes have been seen in the structure of synapses, which have important consequences for the establishment, maintenance of neuronal circuits, and for neuron survival. One of the proteins associated with these failures is postsynaptic densities protein 95 (PSD95), that functions as scaffolding and that shows a drastic decrease during the first stages of the disease, generating cognitive, motor, and behavioral impairments. Our laboratory has developed an epigenetic editing tool known as PSD95-6ZF-VP64, which has shown the ability to bind to the promoter region of the PSD95 gene, promoting its expression, restoring synaptic transmission and dendritic spine density in hippocampal neurons of Alzheimer's disease models. In this study, it is shown that the R6/2 animal, a model capable of recapitulate the main symptoms of Huntington's disease in a short window of time, presents low levels of PSD95 mRNA and protein, which can be reversed by treating the animals with PSD95-6ZF-VP64 after birth. This treatment is also capable of delaying the early symptoms associated with memory and learning, characteristic of the disease, but not reversing the appearance of late symptoms. This evidence suggests that PSD95 would be playing an important role in the early stages of the pathology, one of the longest and most complex phases for patients and their families, which could constitute an attractive therapeutic target for the treatment of the prodromal phase of the disease.
Huntington's disease (HD) is an incurable hereditary pathology caused by an increase in the CAG repeats in exon 1 of the Huntingtin gene. This pathology is associated with a series of motor symptoms, involving an increase in involuntary movements, along with other neuropathological symptoms. The pathophysiology of this disease is associated with a series of events that occur sequentially and whose origin has been traced to the cortico-striatal circuits, from where it spreads to other regions of the brain, particularly the hippocampus. At the cellular level, a series of changes have been seen in the structure of synapses, which have important consequences for the establishment, maintenance of neuronal circuits, and for neuron survival. One of the proteins associated with these failures is postsynaptic densities protein 95 (PSD95), that functions as scaffolding and that shows a drastic decrease during the first stages of the disease, generating cognitive, motor, and behavioral impairments. Our laboratory has developed an epigenetic editing tool known as PSD95-6ZF-VP64, which has shown the ability to bind to the promoter region of the PSD95 gene, promoting its expression, restoring synaptic transmission and dendritic spine density in hippocampal neurons of Alzheimer's disease models. In this study, it is shown that the R6/2 animal, a model capable of recapitulate the main symptoms of Huntington's disease in a short window of time, presents low levels of PSD95 mRNA and protein, which can be reversed by treating the animals with PSD95-6ZF-VP64 after birth. This treatment is also capable of delaying the early symptoms associated with memory and learning, characteristic of the disease, but not reversing the appearance of late symptoms. This evidence suggests that PSD95 would be playing an important role in the early stages of the pathology, one of the longest and most complex phases for patients and their families, which could constitute an attractive therapeutic target for the treatment of the prodromal phase of the disease.
Notas
Tesis (Doctor en Biomedicina)
Financiamiento, de esta tesis fue gracias a los proyectos FONDECYT regular 181645 y 1221745 y beca de financiamiento interno e inicio de investigación UNAB.
Financiamiento, de esta tesis fue gracias a los proyectos FONDECYT regular 181645 y 1221745 y beca de financiamiento interno e inicio de investigación UNAB.
Palabras clave
Proteínas, Análisis, Epigenética, Enfermedad de Huntington, Tratamiento