Descrizione del progetto
Il ruolo dei lisosomi nella diffusione intercellulare dell’α-sinucleina
L’accumulo di aggregati proteici mal ripiegati nelle regioni cerebrali colpite è un segno distintivo condiviso da diverse malattie neurodegenerative (ND, Neurodegenerative Diseases). Nel morbo di Parkinson si accumula alfa-sinucleina (α-syn) mal ripiegata e i meccanismi legati alla diffusione dell’α-syn sono stati implicati nella sua progressione patologica. Studi recenti hanno dimostrato che le fibrille di α-syn si diffondono tra le cellule neuronali attraverso tunnel di nanotubi (TNT), sottili sporgenze di membrana a base di actina che mediano il trasporto intercellulare di vari carichi. Queste fibrille di α-syn inducono l’aggregazione dell’α-syn solubile nelle cellule riceventi. Il progetto LySyT, finanziato dall’UE, svelerà il meccanismo attraverso il quale le fibrille di α-syn fuggono dai lisosomi per indurre l’aggregazione di monomeri nelle cellule accettrici, con l’obiettivo di comprendere la correlazione tra malattie da accumulo lisosomiale e ND.
Obiettivo
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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Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
75724 Paris
Francia