Ricerca Progetti nazionali, regionali, internazionaliNAZIONALIPRIN 2022Decoding distinctive features of EXtracellular

Decoding distinctive features of EXtracellular vesicles In TDP-43 proteinopathies – EXIT

Half of frontotemporal lobar degeneration (FTLD) and almost all amyotrophic lateral sclerosis (ALS) patients are associated with a common histopathology within neurons and glia. This consists in the mislocalisation of the TAR DNA-binding protein 43 (TDP-43) from the nucleus, where it normally resides and plays its function, to the cytosol, where it forms toxic inclusions. TDP-43 aggregation also occurs in an important subset of people affected by Alzheimer's disease (AD), Parkinson’s disease (PD), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA) and inclusion body myopathy (IBM). In all these TDP-43 proteinopathies, TDP-43 undergoes a series of post-translational modifications (i.e. hyper phosphorylation, polyubiquitination and cleavage), resulting in abnormal TDP-43 fragmentation, localization and aggregation. Different disease-associated TDP-43 aggregates are present in affected brain and different structure/composition corresponds to different neurotoxicity. In spite of this acquired knowledge on TDP-43 inclusions, the information on their ultrastructure remains elusive, as well as the mechanism through which inclusions form.

Interestingly, TDP-43 aggregates are able to trigger template-dependent aggregation and amplification of new aggregates, both in in vitro and in vivo models. This aspect is particularly relevant considering that cells release TDP-43 and its disease-associated species as free-proteins and, most importantly, incorporated into lipid bilayer-delimited particles, called extracellular vesicles (EVs). EVs move through biological fluids and can release their content into other cells, therefore they can play a fundamental role in the spreading of TDP-43 proteinopathy. In this context, crucial open questions are whether there is a specific disease-associated TDP-43 cargo transported in EVs, where TDP-43 is localized in EVs (in EVs lumen or associated to the outer corona) and what mechanisms regulate TDP-43 secretion. Taking advantage of our complementary expertise, we design an in-depth analysis of EVs-transported TDP-43 proteins, that involves three levels of investigation: (i) the biophysical level in vitro, (ii) the cell biology in cell cultures, (iii) the characterization of patients-derived samples. Our project intends to identify the structure/composition of TDP-43 species transported into EVs in physiological and pathological condition. Thereafter, it aims at studying how/if TDP-43 EVs harm recipient cell cultures, spreading the TDP-43 proteinopathies. Finally, it aspires to identify a new role of the protein quality control system in extracellular disposal of TDP-43 species. If successful, the project will identify new biomarkers and targets for the development of new therapeutic approaches. Our preliminary data suggest that this ambitious project comes at the most opportune time as we now have tools, materials and knowledge to achieve a step change in TDP-43 research.

 

Data di avvio 18 Ottobre 2023

Data di completamento 18 Ottobre 2025

Total cost  € 110218,00

 

Progetto 2022KSJZF5 finanziato all’interno del Bando PRIN 2022 di cui al Decreto Direttoriale n. 104 del 02/02/2022 nell’ambito del Piano Nazionale di Ripresa e Resilienza, Missione 4 – Componente 2. Dalla Ricerca all’Impresa - Investimento 1.1 Fondo per il Programma Nazionale della Ricerca (PNR) e Progetti di Ricerca di Rilevante Interesse Nazionale (PRIN), finanziato dall’Unione europea – NextGenerationEU – CUP B53D23018750006