Research Projects

Biological phase separation and liquid-like behavior of proteins have drawn unprecedented attention in context of protein condensation diseases. Emerging theories suggest that the phase separated droplets of amyloidogenic proteins are the toxic markers of neurological disorders. However, there is a lack of tractable in vitro and in vivo models to study this phenomenon for therapeutic intervention. This is because the causal proteins are intrinsically disordered and can form heterogeneous condensates with distinct biochemical environments. Morphologically, condensed droplets are indistinguishable and can participate both in cell functions and diseases. The proposed research will determine in detail, the mechanism(s) by which human Tau protein phase separates into different functional and neurotoxic condensates. For this purpose, novel carbon-detected NMR spectroscopic methods will be designed and implemented, to gain atomic-view into Tau condensate heterogeneity. Condensate modifiers are proving to be an attractive promise to intercept disorder protein driven etiologies. Tauopathies present a classical model of condensate mosaic, wherein Tau protein phase separation can be modulated by alternative splicing, post-translational modifications and protein/nucleic acid binding. Aim 1: Investigation of pre-structured motifs within shorter Tau isoforms comprising variable number of C-terminal repeats (3R- and 4R-Tau) in dispersed and condensed phases. Aim 2: Understanding the role of disease-specific hyperphosphorylation on 3R- and 4R- Tau condensation. Aim 3: Evaluation of spatio-temporal localization of 3R- and 4R- Tau condensates under distinct pathophysiological conditions. Outcome of the proposed work will provide streamlined experimental approach to study biomolecular condensation mechanisms involved in difficult-to-treat diseases.