Descripción del proyecto
El papel de los lisosomas en la extensión intercelular de la alfa-sinucleína
La acumulación de agregados proteicos mal plegados en las regiones afectadas del encéfalo representa un elemento distintivo que es compartido por diversos trastornos neurodegenerativos. La alfa-sinucleína (αsin) mal plegada se acumula en la enfermedad de Parkinson, y los mecanismos vinculados a la extensión de la αsin se han implicado en la progresión de la patología. Estudios recientes han demostrado que las fibrillas de αsin se extienden entre las células neuronales a través de nanotubos de tunelización (TNT, por sus siglas en inglés), delgadas protrusiones membranosas basadas en actina que median el transporte intercelular de diversas cargas. Estas fibrillas de αsin inducen la agregación de αsin soluble en las células receptoras. El proyecto financiado con fondos europeos LySyT estudiará el mecanismo a través del cual la αsin escapa de los lisosomas para inducir la agregación de monómeros en las células receptoras, con el objetivo de comprender la correlación entre las enfermedades por depósito lisosomal y los trastornos neurodegenerativos.
Objetivo
Over the last few decades, neurodegenerative diseases (NDs) became one of the top 10 global causes of death. The accumulation of misfolded protein aggregates in affected brain regions is a common hallmark shared by several NDs. Misfolded alpha-synuclein (α-syn) accumulates in Parkinson’s disease (PD), the second most common ND, and recently a “prion-like” mechanism linked to the spreading of α-syn has been suggested for the pathology progression. The Zurzolo group demonstrated that α-syn fibrils spread between neuronal cells inside lysosomes through tunneling nanotubes (TNTs), thin actin-based membrane protrusions mediating intercellular transport of various cargos. As known, lysosomes move along microtubules therefore this research aims to understand how lysosomes can move inside and through actin-based TNTs. The host lab also showed that the transferred α-syn fibrils induce the aggregation of soluble cytosolic α-syn in receiving cells and this project will unravel the mechanism by which α-syn fibrils escape from lysosomes to induce the aggregation of monomers in acceptor cells. In addition, since lysosomal dysfunction is a common feature of NDs, this research will shed light on the functionality and fate of α-syn-loaded lysosomes. Lysosomal dysfunction is also a trait of Lysosomal Storage Diseases (LSDs), a group of about 50 rare inherited metabolic disorders generally caused by the defective function of a specific lysosomal enzyme leading to the lysosomal accumulation of non-degraded materials and neurodegeneration in the forms most severe. This project will investigate the correlation between LSDs and NDs and the possible implications of TNTs in LSDs that represent a new perspective for LSDs etiopathogenesis. By combining my skills in lysosome physiopathology and the host lab expertise in TNTs and PD pathogenesis, this project will provide a deep understanding of the role of lysosomes in NDs pathogenesis and valuable insights to combat these incurable diseases.
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
75724 Paris
Francia