UNTauANGLE: Untangling the biophysics of tau aggregation through computational modelling

Tauopathies, such as Alzheimer’s and Pick's disease are a large class of dementias that are tightly linked to the dysfunction of tau protein. The dysfunction of tau includes the formation and runaway growth of multi-protein clumps that result in severe damage to neurons. There is still no effective treatment for tauopathies caused by excessive clumping of tau, largely due to a lack of basic understanding of the molecular interactions and conditions in the neuron that dysregulate tau. These include the crowding of other proteins, post-translational modifications, interactions with extracellular vesicles, and the thermodynamic barriers that tau must overcome to form clumps. Disease, neurons, and proteins are generally the subjects of biology, yet the molecular interactions and processes that govern tau are the subjects of physics. Thus, understanding tau dysfunction and how this connects to disease requires a synergy of biological and physical perspectives. In this project, we will build a theoretical modelling framework to understand how all the salient molecular interactions and reactions between tau and other molecules affects how tau clumps together. Importantly, we will work closely with experts in experimental cell biology and chemical physics to highlight physical mechanisms that will help target effective therapeutics.