Grant: CIHR Fellowship

The build-up of pathological aggregates in the brain comprised of the tau protein is a clinical hallmark of Alzheimer's disease (AD). The progression of AD is closely associated with the spreading of tau aggregates i.e. neurofibrillary tangles (NFTs), through anatomically connected regions of the brain, suggesting that tau is a major driver of AD pathology. A notable discrepancy with the clinical presentation of NFTs is that tau is a highly soluble protein in solution and exhibits very low tendency to aggregate. Recent studies have proposed an unconventional pathway through which tau overwhelms its native high solubility. It has been demonstrated that in the presence of RNA, tau undergoes liquid-liquid phase separation (LLPS), forming liquid droplets that condense high concentrations of tau into a relatively confined space. The supersaturation of tau in turn promotes its conversion into solid-like toxic aggregates. However, LLPS is also involved in the regulation of normal biology, such as the translation of genes into proteins. Therefore, it remains unclear how the phase separated systems involved in gene regulation differ from those promoting the formation of pathological aggregates. Critical to distinguishing these two opposing cases is determining the arrangement of protein building blocks i.e. amino acids, involved in phase separation vs. transition from liquid droplets into solid fibers. Such maps are essential for the development of therapeutics selectively targeting abnormal condensates, with minimal off-target effects. Here we propose to uncover these amino acids networks using a combination of Nuclear Magnetic Resonance spectroscopy and light microscopy techniques that break the resolution barrier for the description of abnormal phase separated systems. Importantly, these studies will be performed in the presence of age-related stress factors to gain an understanding of how aging contributes to the disease process and how we can prevent it.