TEAM - Role of TDP-43 self-assembly in health and disEase: molecular characteristics, cellular Aspects and animal Models
The aggregation of the TAR DNA-binding protein 43 (TDP-43) into intraneuronal inclusions is strongly associated with a number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and tau-negative ubiquitin-positive frontotemporal lobar degeneration (FTLD-U or FTLD-TDP). The function of TDP-43 is primarily solved in the nucleus, where it plays broad roles in DNA transcription control, whereas, upon translocation into the cytoplasm, TDP-43 has been associated with the formation of stress granules through phase separation. While the pathological relevance of TDP-43 aggregation in neurodegeneration is now established, its role in the mechanisms of neurotoxicity associated with ALS/FTLD remains obscure.
In this context, a crucial open question is how the balance between functional and pathological self-assembly of TDP-43 is regulated. This proposal aims at the ambitious goal of elucidating this subtle equilibrium at different levels of biological complexity. A multilayered and multidisciplinary project will delineate the link between the molecular, cellular and in vivo properties of TDP-43 under physiological conditions and under circumstances that lead to its aberrant aggregation. By assembling an interdisciplinary team, we are uniquely positioned to employ a large spectrum of techniques to perform investigations on different biological scales ranging from the structure of TDP-43 monomer, dimer and aggregates to the characterization of the mechanisms of toxicity that these generate in neurons and in animal models.
With this worldclass experimental platform, our collaborative research will clarify i) the structure of functional monomeric and dimeric forms of TDP-43 and of its aberrant oligomeric and fibrillar species, 2) the nature of the cellular damage generated by TDP-43 aggregation in various neuronal types and 3) the underlying mechanisms by which these aggregates induce toxicity and pathology upon infusion in animal models. It is crucially important that these goals are achieved by investigating the biology and pathology of TDP-43 from different angles and ranging from the molecular to the system level, which is a distinctive characteristic of our interdisciplinary team. If successful, the project will have a transformative impact on our understanding of TDP 43 to reveal how neurodegeneration arises in ALS/FTLP. 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 25 Aprile 2022
Data di completamento 25 Aprile 2025
Total cost €162896,00
Ultimo aggiornamento
28.05.2024