NMR spectroscopy of Tau, a naturally unfolded protein
The neuronal tau protein is associated with tauopathies, most notably Alzheimer’s disease (AD). tauopathies are characterised by intraneuronal aggregation of tau protein into filaments causing neurofibrillary degeneration and synaptic dysfunctions, which lead to dementia. The urgent need for better diagnostics for AD and related tauopathies, as well as disease-modifying treatments, is immense due to the expected growing burden link to demographic changes. Our aim is to understand the relationship between phosphorylation and cellular dysfunctions induced by tau pathogenesis, based on collaborations with experts in the AD field in Lille, combining our complementary approaches to decipher key mechanisms of tau dysregulation. The team was the first to publish on NMR signal assignments of tau (Lippens et al., 2004; Smet et al., 2004). In addition, in a milestone paper, we showed the potential of nuclear magnetic resonance spectroscopy to characterize protein phosphorylation, a methodology that has been widely adopted nowadays (Landrieu et al., 2006). Our focus of interest is the impact of phosphorylation on tau structure and function. We have investigated the impact of tau phosphorylation on its interaction with physiological partners, such as the AD genetic determinant Bin1 (Sartori et al., 2019, Lasorsa et al. 2018, Malki et al., 2017, Sottejeau et al., 2015), the link between phosphorylation and conformational perturbation of tau (Ahuja et al., 2016, Gandhi et al., 2015) and finally the relation between specific phosphorylation of tau and its aggregation susceptibility ( Despres et al., 2019, Despres et al., 2017; Qi et al., 2016). We have also investigated modulation of protein-protein interaction, involving phospho-Tau epitopes, using peptide-based compounds (Andrei et al., 2018, Milroy et al., 2015; Smet et al., 2005). Another strategy to slow down Tau aggregation is the use of single domain antibodies (Dupré et al., 2019) and monoclonals (Albert et al., 2019) targeting the central region of tau.
Our project is supported by the ANR ToNIC, ANR PykAlz, ISite ULNE Tunable and the Labex Distalz
Contact: isabelle.landrieu@univ-lille.fr
