Publication: Relevancia del receptor cannabinoide CB2 en la esclerosis lateral amiotróficca (ELA)
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2019-02-12
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Lago Femia, Eva de
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Universidad Complutense de Madrid
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Abstract
La Esclerosis Lateral Amiotrófica (ELA) o “Amyotrophic Lateral Sclerosis” (ALS) en inglés, es una enfermedad neurodegenerativa en la que se produce la muerte de las motoneuronas superiores e inferiores. Estas neuronas son las encargadas de transmitir el impulso nervioso hacia los músculos permitiendo el movimiento. A lo largo que la enfermedad evoluciona, se produce una debilidad progresiva en las extremidades (suele afectar primero a un tipo para extenderse al otro) y una consecuente debilidad muscular. Esto conlleva a una atrofia de los músculos y en etapas finales a una parálisis total, lo que provoca normalmente una insuficiencia respiratoria que lleva a la muerte del paciente. A día de hoy y como ocurre con otras enfermedades neurodegenerativas, sigue sin haber un tratamiento eficaz para la ELA. Durante años, el único fármaco aprobado para su prescripción ha sido el riluzol, pero ha demostrado una escasa efectividad. La prevalencia de la enfermedad muestra que aproximadamente 2 personas de cada 100.000 padecen la ELA, siendo más frecuente la afección en hombres que mujeres con un ratio 3 a 1. Alrededor de un 90% son casos esporádicos, dejando el restante 10% de origen familiar. En cualquiera de los dos casos, se han identificado múltiples mutaciones asociados a la ELA. En los años noventa la primera mutación que se identificó fue en el gen de la proteína SOD1, lo que ha hecho que sea la más estudiada. No fue hasta el año 2006 cuando también se identificó a TDP43 como otra proteína cuya mutación se asocia a la ELA (y a la demencia frontotemporal). En estos últimos años otros genes se han ido añadiendo a la lista de mutaciones implicadas, como FUS, o de manera más relevante el gen C9ORF72. La mayoría de las mutaciones en estos genes producen un plegamiento erróneo proteico y en consecuencia, fallos funcionales que desencadenan múltiples eventos citotóxicos que desencadenan la muerte de las motoneuronas. Entre esos eventos, se puede encontrar una marcada activación glial asociada a un incremento de la inflamación; fallos en la respiración celular que desencadenan estrés oxidativo; exceso de glutamato en las sinapsis que promueven una excitotoxicidad, etc. Esta amplia patogénesis en la que los diversos eventos tóxicos se suman y se complementan, dificultan el poder encontrar un tratamiento eficaz para la ELA...
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease in which the upper and lower motorneurons die. These neurons are responsible for transmitting the nerve impulse to the muscles allowingmovement. As the disease progresses, there is progressive weakness in the extremities (usually affecting onetype first to spread to the other) and consequent muscle weakness. This leads to atrophy of the muscles andin final stages to a total paralysis, which usually causes a respiratory failure that leads to the death of thepatient. Today, there is still no effective treatment for ALS, as other neurodegenerative diseases. For years,the only drug approved for prescription has been riluzole, but it has shown little effectiveness. The prevalenceof the disease shows that approximately 2 people in 100,000 suffer ALS, being more frequent in men thanwomen with a ratio of 3 to 1. Around 90% are sporadic cases, leaving the remaining 10% of family origin. Ineither case, multiple mutations associated with ALS have been identified. In the nineties the first mutationthat was identified was in the SOD1 protein gene, which has made it the most studied case. It was not until2006 that TDP43 was also identified as another protein whose mutation is associated with ALS (andfrontotemporal dementia). In recent years other genes have been added to the list of mutations involved,such as FUS, or more significantly the C9ORF72 gene. The majority of the mutations in these genes producea protein missfolding and consequently, functional failures associates with multiple cytotoxic events thattrigger the death of motor neurons. Among these events, one can find a marked glial activation associatedwith an increase in inflammation; failures in cellular respiration that trigger oxidative stress; excess ofglutamate in the synapses that promote an excitotoxicity, etc. This broad pathogenesis in which the various..
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease in which the upper and lower motorneurons die. These neurons are responsible for transmitting the nerve impulse to the muscles allowingmovement. As the disease progresses, there is progressive weakness in the extremities (usually affecting onetype first to spread to the other) and consequent muscle weakness. This leads to atrophy of the muscles andin final stages to a total paralysis, which usually causes a respiratory failure that leads to the death of thepatient. Today, there is still no effective treatment for ALS, as other neurodegenerative diseases. For years,the only drug approved for prescription has been riluzole, but it has shown little effectiveness. The prevalenceof the disease shows that approximately 2 people in 100,000 suffer ALS, being more frequent in men thanwomen with a ratio of 3 to 1. Around 90% are sporadic cases, leaving the remaining 10% of family origin. Ineither case, multiple mutations associated with ALS have been identified. In the nineties the first mutationthat was identified was in the SOD1 protein gene, which has made it the most studied case. It was not until2006 that TDP43 was also identified as another protein whose mutation is associated with ALS (andfrontotemporal dementia). In recent years other genes have been added to the list of mutations involved,such as FUS, or more significantly the C9ORF72 gene. The majority of the mutations in these genes producea protein missfolding and consequently, functional failures associates with multiple cytotoxic events thattrigger the death of motor neurons. Among these events, one can find a marked glial activation associatedwith an increase in inflammation; failures in cellular respiration that trigger oxidative stress; excess ofglutamate in the synapses that promote an excitotoxicity, etc. This broad pathogenesis in which the various..
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Tesis de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Bioquímica y Biología Molecular, leída el 17-04-2018