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Persulfidación de proteínas: el eslabón perdido en los mecanismos de defensa contra la enfermedad de Alzheimer
Ya-Nan Ma1, Xiaoxi Huang2, Ying Xia3
1Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, China.
Drug discoveries & therapeutics
|February 8, 2026
Resumen
La enfermedad de Alzheimer puede deberse a una reducción de la señalización del sulfuro de hidrógeno (H₂S), no solo a la beta-amiloide. La restauración de las vías de H₂S, en lugar de la simple suplementación, ofrece un nuevo enfoque de medicina de precisión para la neuroprotección.
Área de la Ciencia:
- Neurociencia
- Bioquímica
- Patología
Sus antecedentes:
- Los tratamientos para la enfermedad de Alzheimer (AD) carecen de avances a pesar de la extensa investigación sobre la beta-amiloide.
- Se propone el colapso de la señalización endógena del sulfuro de hidrógeno (H₂S) como un fallo clave en los mecanismos de defensa del cerebro contra la AD.
Objetivo del estudio:
- Presentar un paradigma patológico alternativo para la AD centrado en la señalización de H₂S.
- Explorar el papel de la deficiencia de cistationina γ-liasa (CSE) y su impacto en la fosforilación de Tau.
- Proponer un marco de medicina de precisión para restaurar la señalización de H₂S en la AD.
Principales métodos:
- Disección de la cascada molecular que involucra la deficiencia de CSE y la persulfidación de GSK3β.
- Análisis del metabolismo de la transsulfuración, la función mitocondrial y el estado nutricional.
- Integración de estos análisis para proponer un marco terapéutico novedoso.
Principales resultados:
- La reducción de la señalización de H₂S, debida a la deficiencia de CSE, conduce a una disminución de la persulfidación de GSK3β.
- Esta reducción promueve directamente la hiperfosforilación de Tau y la consiguiente lesión neuronal.
- La suplementación simplista de sulfuro puede plantear riesgos de toxicidad debido a la estrecha ventana terapéutica y los efectos horméticos del H₂S.
Conclusiones:
- La restauración de la señalización endógena de H₂S, no solo la suplementación de sulfuro, es crucial para la neuroprotección en la AD.
- Se necesita un enfoque de medicina de precisión dirigido a la restauración de H₂S específica del cerebro.
- Esto cambia el enfoque de la investigación de la AD de la eliminación de agregados de proteínas a la mejora de la resiliencia neuronal.
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