Aggregation of the C-terminal fragment of the TAR DNA-binding Protein 43 (TDP-43) in relation to the Amyotrophic lateral sclerosis (ALS)

Many neurodegenerative diseases -including the Amyotrophic Lateral Sclerosis (ALS) - are associated with the presence of protein aggregates. Over 97% of ALS cases feature pathological inclusions mainly composed by the protein TDP-43 and affect the cortical and spinal neurons. This thesis studies the aggregation process of the two types of TDP-43 C-terminal fragments (CTFs) - corresponding to different cleavages of the full protein- that can be found in the former. This is interesting not only for the possible implications on the ALS disease, but also because TDP-43 fragments are a useful system model for protein aggregation. The interaction model proposed in this work starts from a cross-beta spine model, which hypothesizes that the CTFs' RRM2 fragment is at the core of the aggregation, thanks to the exposition of the aggregation prone beta-strands following the proteolysis. By designing specific interfering aptamers which can bind to the RRM2 binding regions, we should be able to prevent another CTF to bind to that site. Still, the structures of these fragments have not been deeply studied yet and their conformations are not available and difficult to study experimentally. To propose some possible binding regions, we study the RRM2 fragments with Molecular Dynamics simulations. By applying a cluster analysis on the two-principal components projections of the resulting trajectories, we find the fragments' equilibrium conformations. Next, we verify the shape complementarity between the 3D molecular surfaces of these equilibrium configurations by means of the 2D Zernike polynomial expansion. Among the Zernike selected binding regions, we select the ones that would be able to bind an aptamer. In the future, we will verify our conclusions with Brillouin microscopy: if the suggested binding regions are really at the core of the aggregation, following the insertion of expressively designed aptamers, the number and dimension of aggregates will decrease.