Project description DEENESFRITPL The role of lysosomes in the intercellular spreading of α-synuclein The accumulation of misfolded protein aggregates in affected brain regions is a hallmark shared by several neurodegenerative diseases (ND). Misfolded alpha-synuclein (α-syn) accumulates in Parkinson’s disease, and the mechanisms linked to the spreading of α-syn have been implicated in its pathology progression. Recent studies have demonstrated that α-syn fibrils spread between neuronal cells through tunnelling nanotubes (TNTs), thin actin-based membrane protrusions mediating the intercellular transport of various cargoes. These α-syn fibrils induce the aggregation of soluble α-syn in receiving cells. The EU-funded LySyT project will uncover the mechanism by which α-syn fibrils escape from lysosomes to induce the aggregation of monomers in acceptor cells, aiming to understand the correlation between lysosomal storage diseases and NDs. Show the project objective Hide the project objective Objective 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. Fields of science natural sciencesbiological sciencesneurobiologymedical and health sciencesbasic medicinepathologymedical and health sciencesbasic medicineneurologyparkinsonnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Keywords lysosome tunneling nanotubes alpha-synuclein cell-cell communication lysosomal dysfunction lysosomal storage diseases Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2019 - Individual Fellowships Call for proposal H2020-MSCA-IF-2019 See other projects for this call Funding Scheme MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF) Coordinator INSTITUT PASTEUR Net EU contribution € 184 707,84 Address RUE DU DOCTEUR ROUX 25-28 75724 Paris France See on map Region Ile-de-France Ile-de-France Paris Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 184 707,84