Descripción del proyecto
Dilucidación de la fragmentación del aparato de Golgi
El aparato de Golgi es un orgánulo de las células eucariotas que procesa y clasifica proteínas destinadas a la membrana de plasma o a la secreción. Por consiguiente, desempeña una función esencial en la homeostasis celular y la comunicación entre células. El aparato de Golgi es un orgánulo extremadamente dinámico que mantiene una morfología específica, pero se fragmenta irreversiblemente en afecciones neurodegenerativas como la enfermedad de Alzheimer. El objetivo del proyecto financiado con fondos europeos UbiGolD es investigar los mecanismos que regulan la fragmentación del aparato de Golgi. Los investigadores se centrarán en un nuevo mecanismo de degradación proteasomal y en la función que desempeña para la integridad del aparato de Golgi en condiciones cambiantes. Los resultados arrojarán luz sobre la neurodegeneración y allanarán el camino hacia nuevos tratamientos.
Objetivo
Alzheimer’s disease (AD) is the most common neurodegenerative disorder which affects 47 million patients worldwide. However, the underlying molecular mechanisms leading to sporadic-AD remain unknown and preventive treatment is not yet available. Lately, the ubiquitin-proteasome system has been implicated in AD. Dr. Merbl’s laboratory recently discovered a novel mechanism of Golgi-localized proteasomal degradation that controls Golgi integrity under stress. As the Golgi apparatus is the major hub required for protein secretion and plasma membrane localization, its proper function is crucial for maintaining cellular homeostasis and controlled cell-cell communication. This intriguing finding may be of instrumental importance to evidence of Golgi fragmentation which is observed in neurons in neurodegeneration diseases including AD as the Merbl lab identified that the ubiquitin-proteasome system is required for Golgi fragmentation.
My goal is to identify regulatory mechanisms of ubiquitin E3 ligases that are involved in Golgi fragmentation in neurons. Specifically, I aim to identify critical determinants that regulate Golgi homeostasis and integrity under changing pH and calcium concentration and decipher their role in AD using CRISPR gene manipulation, pH-dependent immunofluorescence and biochemical methods and state-of-the-art proteomic and glycomic techniques. Elucidating ubiquitin-dependent regulation of Golgi fragmentation in neurodegeneration and AD would advance our understanding not only of Golgi biology and provide new possibilities for therapeutic intervention for neurodegeneration.
Ámbito científico
Programa(s)
Régimen de financiación
MSCA-IF-EF-ST - Standard EFCoordinador
7610001 Rehovot
Israel