Munari, Francesca
Abstract:
Impact of ubiquitination on the aggregation of Tau protein, a key player in Alzheimer’s disease
Topic:
The microtubule associated protein Tau is a cytosolic protein, mainly found in neurons axon, that promotes the assembly and stability of microtubules (MT), and contributes to the regulation of axonal stability and transport, neurite outgrowth and synaptic function (1). Tau is considered a key player in the neurodegenerative process underlying Alzheimer’s disease (AD) and other tauopathies due to its capability to convert into toxic amyloidogenic species and self-assemble into straight and paired helical filaments (PHFs) that are found in the neurofibrillary tangles (NFTs), the defining pathological hallmark of AD (1). Since Tau extracted from PHFs was consistently found modified with specific post-translational modifications (PTMs) (1-3), the understanding of their role in Tau aggregation and altered activity may help to identify key mechanisms of Tau-mediated toxicity. Tau from AD-PHFs was found ubiquitinated at several lysine residues within the microtubule binding domain (MBD) that is also the part of the protein that form the core of the fibrils (2,3). Ubiquitination would normally regulate Tau clearance by autophagic and proteasomal pathways. However, in pathological condition, ubiquitinated Tau aggregates are not efficiently removed and accumulate within neuronal cells with potential toxic effects. In our work (4,5) we have ubiquitinated the MBD of Tau protein by a semisynthetic approach, based on the chemical conjugation of proteins precursors, that allowed us to obtain homogenous ubiquitination of Tau at unique and precise sites. Specifically, we produced three ubiquitinated tau isomers with linkages in positions 254, 311 and 353 as representatives of the ubiquitinated Tau species found in AD-PHFs. By biophysical studies we have elucidated the impact of mono- and poly- ubiquitination on the mechanism of aggregation of Tau protein, revealing that the different conjugates exhibit diverse capability to form filaments and that the effect of the modification is site dependent. Interestingly, ubiquitination at residue 311 had the strongest effect in interfering with the Tau conformational transitions that progress towards amyloid formation.
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