Dr. David Westaway

Chemistry and initiation of


protein misfolding



PhD: Biochemistry, Imperial College, University of London, United Kingdom

Post-doctoral training: Neurology and Microbiology & Immunology, UCSF, CA

Position: Professor

Division of Neurology, Department of Medicine Centre for Prions and Protein Folding Diseases Neuroscience and Mental Health Institute Faculty of Medicine & Dentistry

Email: david.westaway@ualberta.ca Lab webpage: http://www.prioncentre.ca/people/westaway

Selected publications

Daude, N., Wohlgemuth, S., Pitstick, R., Gapeshina, H., Carlson, G. A. , and Westaway, D. “Knockout of the PrP- like Sprn gene does not produce embryonic lethality in combination with PrPC-deficiency” Proceedings of the National Academy of Sciences USA, 2012 109:1035- 1040.

Mays CE, Kim C, Haldiman T, van der Merwe J, Lau A, Yang J, Grams J, Di Bari MA, Nonno R, Telling GC, Kong Q, Langeveld J, McKenzie D, Westaway D, Safar JG. Prion disease tempo determined by host-dependent substrate reduction. J Clin Invest. 2014 124(2):847-58.

Lau A, McDonald A, Daude N, Mays CE, Walter E, Wohlgemuth S, Yang J, Shi B, van der Merwe J, Gapeshina H, Kim C, Grams J, Wille H, Balachandran A, Schmitt-Ulms G, Safar J, Millhauser G, Westaway D. “Octarepeat region flexibility impacts prion function, endoproteolysis and disease manifestation”. EMBO Mol. Med. 2015 Feb 6; 7(3): 339-56.

Mays CE, van der Merwe J, Kim C, Jaldiman T, McKenzie D, Safar JG, Westaway D. (2015) “Prion Infectivity Plateaus and Conversion to Symptomatic Disease Originate from Falling Precursor Levels and Increased Levels of Oligomeric PrPSc Species”. J Virol. Dec 15;89(24): 12418- 26.


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.

Current Research:

1)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.

3)PrP endoproteolysis. Fragmentations affect the ability of PrPC to be converted to the disease-associated isoform PrPSc or transduce the toxic effects of misfolded PrP or oligomeric amyloid beta peptide. We are using a novel genetic system to interrogate the two endoproteases that control whether PrPC forms the benign or pathogenic fragments called C1 and C2, respectively.

4)Tau and tauopathies Based on human anatomical mapping and mouse data certian brain regions have a special vulnerability to accumulating misfolded and hyperphosphorylated forms of Tau. Using low-expresser Tau transgenic mice we will perform a systematic screen of pharmacological, polypeptide and chemical agents that foster Tau neuropathology in these regions. For treatments that accentuate Tau accumulation, we will allow pathology to spread in the CNS and misfolded Tau to amplify by templated misfolding; by this means we will accumulate material for chemical profiling of aberrant Tau species.