Research area: Inhalation Drug Delivery

Research sponsor: EPSRC

Project overview

Protein and Protein Interaction Characterisation in the Context of Alzheimer’s disease

Understanding protein and how they interact with each other is key in pathological study of diseases involving an abnormal form of proteins (e.g. bovine spongiform encephalopathy). While crystallography remains the most thorough 3D structural determination method, its application is still significantly limited by the crystallisation step: obtaining a well-diffracting crystal. Other characterisation methods such as mass spectroscopy have made significant progress in the recent decades and are not constrained by the crystallisability of protein molecules themselves.

Alzheimer’s disease (AD) is essentially a neurodegenerative disease that ultimately leads to death and is characterized by progressive cognitive decline. Neurofibrillary tangles (NFTs) and amyloid plaques are deemed as the two hallmarks of AD. These two special features are, by nature, protein aggregation.

NFT essentially forms from aggregation of an abnormal microtubule associated protein (MAP), known as protein tau. Pathology study centered on protein tau is named ‘taupathology’, which is the focus of this work.Tandem mass spectrometry and compactable crosslinking technique will be applied to study the PTM of Tau and Tau-Tau interaction in aggregation.

Crystallisation trails will be conducted and technique will be refined. The breakdown objectives are: 1) develop in cell model for AD taupathology; 2) characterise phosphorylation profile of normal tau and AD tau to understand its role in AD by MS. 3) conducting crystallisation trail, proceed to optimising crystal quality and structural determination if primary outcome is promising, otherwise, work on further improving crystallisation technique will be carried out.