TubInTrain · Tuning Tubulin Dynamics and Interactions to Face Neurotoxicity: a Multidisciplinary Approach for Training and Research

Tuning Tubulin Dynamics and Interactions to Face Neurotoxicity: a Multidisciplinary Approach for Training and Research

The improvements in life expectancy in the Western societies have turned neurodegenerative diseases and cancer into the most common health problems of the European Union. It is therefore of outmost importance to find and optimize tools that can contribute to the full comprehension of the molecular mechanisms involved in the progression of these pathologies. Microtubules a) are formed by polymerization of the globular proteins alpha- and beta-tubulin; b) present a structure that is regulated by a polymerization-depolymerization dynamic process; c) are biological entities that play an important role in a number of cellular processes including also cell division; d) interact with other proteins and this interaction is relevant for different cellular functionalities such as neuronal activity. Changes in the behaviour and organization of microtubules are emerging as relevant events associated with many neurodegenerative diseases. Deciphering the very basic biological mechanisms of neuronal damage linked to tubulin/microtubule perturbation is a challenge for facing neurodegeneration and in particular for the design of possible compounds that could reduce the effect of the neurological diseases. The aim of TubInTrain was to investigate the role of microtubules in neuron functionality through an interdisciplinary approach that is mandatory for a better comprehension of microtubules involvement in the pathogenic mechanisms of neurodegeneration. TubInTrain involved research groups that belongs to different scientific area such as chemistry, biology and computer science (Fig.1). All the scientific progresses in this subject, are giving important information for the design of therapeutic interventions, thus making this project in line with the aim of Horizon 2020 programme [Challenge “Health, demographic change and wellbeing”]. In particular, we investigated different strategies for tuning tubulin dynamics and the interactions of microtubules with other proteins with the aim to: i) model and evaluate the impact of different classes of small molecules (obtained by chemical synthesis or extracted by natural sources as secondary metabolites) on tubulin/microtubules at atomic level in cell free system, ii) model and evaluate the impact of two tubulin interacting proteins (Tau and alpha-Synuclein) on tubulin/microtubules at atomic level in cell free system, iii) determine the effects of the above compounds on microtubule dynamics, protein-microtubule interaction, protein aggregation and metabolism in peripheral neurons and in cellular models of neurodegeneration. The research activities were articulated into three Work Packages (WP1-WP2-WP3 - Fig.2)

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