David Westaway

Biography

My lab's goal is to understand molecular events that cause the most common forms of neurodegenerative disease and thus inform the translational outcomes of diagnosis and therapy. Most dementia cases occur on a one-by-one basis without affected relatives, a pattern of appearance called "sporadic" or "idiopathic". Starting with natively folded precursor proteins such as the cellular prion protein (PrPC), accumulation of misfolded protein forms of these substrates is an accepted end-stage feature of many dementias; however, we have a poor understanding of the chemical events that trigger sporadic disease and we lack animal models that capture these events. We are using knowledge of infectious and genetic prion diseases to open the black box of sporadic prion disease, by looking at early misfolding events and proteolytic clearance pathways. We are also investigating the microtubule-associated protein Tau, which can also misfold and is associated with other dementias; here we are again interested in rare events that may mark the very beginnings of the disease process.

Research Interest

Early misfolding To discern the origins of sporadic prion disease, we will use chemical modification to probe motifs in PrPC's central region that may facilitate multimerization and early misfolding events that then go on to invade the C-terminal globular domain. 2)Proteostasis. We have published that protein levels of PrPC and its CNS-expressed paralog Shadoo are markedly reduced early on in prion infections, well before any neuronal loss is apparent. This unexpected effect may indicate a protective host response acting at the cellular level. Using prion-infected cells, antibiotics that affect protein synthesis and clearance, genetic interventions and analyses of protein trafficking we will determine whether down-regulation occurs by a) the proteasome system), b) autophagy, c) a hybrid of (a) + (b), or d) by a novel system.