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Poly ((ADP-ribosa) conduce a la neurodegeneración patológica de la α-sinucleína en la enfermedad de Parkinson
Tae-In Kam1,2,3, Xiaobo Mao1,2,3, Hyejin Park1,2,3
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Science (New York, N.Y.)
|November 3, 2018
Resumen
La alfa-sinucleína patológica en la enfermedad de Parkinson activa PARP-1, acelerando la formación de proteínas tóxicas y la muerte neuronal. La inhibición de PARP-1 es prometedora para prevenir la pérdida de neuronas de dopamina en la enfermedad de Parkinson.
Área de la Ciencia:
- La neurociencia
- La bioquímica
- Patología
Sus antecedentes:
- La enfermedad de Parkinson (EP) se caracteriza por la acumulación y agregación de alfa-sinucleína (α-syn).
- Los mecanismos moleculares precisos que impulsan la neurodegeneración en la EP siguen sin estar claros.
Objetivo del estudio:
- Investigar el papel de la poliadenosina 5'-difosfato-ribosa (PAR) polimerasa-1 (PARP-1) en la patogénesis de la enfermedad de Parkinson.
- Elucidar los mecanismos moleculares que vinculan la agregación α-syn con la neurodegeneración.
Principales métodos:
- Investigó la activación de PARP-1 por α-syn patológico.
- Se evaluó el impacto de la generación de PAR en la agregación y toxicidad de la α-syn.
- Utilizó inhibidores de PARP y eliminación genética de PARP-1 en modelos celulares.
- Se midieron los niveles de PAR en el líquido cefalorraquídeo y el tejido cerebral de pacientes con EP.
Principales resultados:
- La α-syn patológica activa la PARP-1, lo que lleva a una mayor generación de PAR.
- La generación de PAR acelera la formación de α-syn patológico, induciendo la muerte celular a través del partenato.
- La inhibición o eliminación de la PARP-1 mitigó la toxicidad α-syn.
- Se identificó un bucle de transmisión en el que el PAR aumenta la toxicidad de la α-syn.
- Se observaron niveles elevados de PAR en el líquido cefalorraquídeo y el cerebro de los pacientes con EP.
Conclusiones:
- La activación de PARP-1 es un mediador clave de la toxicidad α-syn y la neurodegeneración en la EP.
- PARP-1 representa un objetivo terapéutico potencial para la enfermedad de Parkinson.
- La inhibición de PARP-1 puede ofrecer una estrategia modificadora de la enfermedad para preservar las neuronas de dopamina en la EP.
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