Investigating components implicated in Alzheimer’s disease and other tauopathy pathogenesis (360G-Wellcome-203978_Z_16_A)

Tauopathies including Alzheimer’s are widespread neurodegenerative diseases which cause progressive decline in cognition and yet the mechanisms driving the pathogenesis remain obscure. Central to these diseases is the protein Tau. In normal conditions, Tau locates to axons, cable like cellular structures that wire the brain. However, during tauopathies the behaviour of Tau is altered, Tau detaches from axons, instead it occupies other parts of the neuron and forms aggregates. During this process, Tau becomes unconnected from its normal protein partners and instead it associates and sequesters other factors. The nature of these toxic interactions is unknown. Here we will investigate how the network of proteins surrounding Tau changes during disease by using a new technique referred to as BioID2. For this, we will engineer Tau (by attaching BirA) so that it adds a tag (biotin) to proteins in close proximity to facilitate their isolation and identification. BioID2 will be performed in already well stablished models of tauopathies in Drosophila, because it’s genes and proteins can be manipulated with ease and are similar to that of humans. The outcome will be a comprehensive understanding of how Tau interactions changes in pathogenic conditions, giving insight into Tau toxicity and novel therapeutic targets.