Dr. Holger Wille

PhD: Max-Planck Unit for Structural Molecular

Biology & University of Hamburg (Germany)

Post-doctoral training: University of California, Department of Neurology, San Francisco, California, USA

Position: Associate Professor

Department of Biochemistry Centre for Prions and Protein Folding Diseases Faculty of Medicine & Dentistry

E-mail: wille@ualberta.ca

Selected publications

Wille, H, Bian, W, McDonald, M, Kendall, A, Colby, DW, Bloch, L, Ollesch, J, Borovinskiy, AL, Cohen, FE, Prusiner, SB, and Stubbs, G (2009). Natural and synthetic prion structure form X-ray fiber diffraction. . Proceedings of the National Academy of Sciences USA . 9: 106, 16990-16995

Requena, JR and Wille, H (2014). The structure of the infectious prion protein: Experimental data and molecular models. Prion. 8, 60-66.

Godsave, SF, Peters, PJ, and Wille, H (2015). Subcellular distribution of the prion protein in sickness and in health.Virus Research, 207, 136-145.

Vázquez-Fernández, E, Vos, MR, Afanasyev, P, Cebey, L, Sevillano, AM, Vidal, E, Rosa, I, Renault, L, Ramos, A, Peters, PJ, Fernández, JJ, van Heel, M, Young, HS, Requena, JR, and Wille, H (2016). The structural architecture of an infectious mammalian prion using electron cryomicroscopy.PLoS Pathogens 12, e1005835. 

Tackling prion disease based on prion protein shape, size, and disease stage


The general focus of the research in my laboratory is the structure of amyloids and other disease-related, misfolded proteins. In particular, we are interested in the infectious prion protein (PrPSc) and the structure-function relationship underlying its infectious nature. In recent years, mounting evidence has implicated prion-like mechanisms in other neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Lou Gehrig’s disease, to name just a few. The mechanistic similarities that connect these diseases and the archetypical prion diseases are promising research areas for future investigations. In my laboratory, the scope of our experimental approaches is centered on electron microscopy, supplemented by other biochemical and biophysical methods, and molecular modeling. Many of our experiments are carried out as interdisciplinary collaborations with other scientists from the University of Alberta and from other universities and research institutions nationally and internationally.  

Current Research

1)Prion structure The molecular structure of PrPSc is one of the main unsolved questions in the prion field. Our earlier investigations using X-ray fiber diffraction (Wille et al., 2009) indicated that the molecular architecture of PrPSc is based on a four-rung β-solenoid structure. This finding contradicted most molecular models that were proposed for the structure of PrPSc. In our most recent study (Vázquez-Fernández et al., 2016), we used electron cryomicroscopy to visualize individual PrPSc amyloid fibrils. Image processing allowed us to generate three-dimensional reconstructions of single PrPSc amyloid fibrils, which, again, revealed a four-rung β-solenoid as the basic fold for the infectious prion. Current projects focus on analyzing the structure of prion fibrils from human, animal, and recombinant sources.

2)Structural mimics

We are also studying details about the prion protein structure itself. We want to better understand how prion protein can take on different shapes and how these shapes affect how toxic and infectious the prion protein becomes. In particular, we want to know whether the prion disease of deer and elk, Chronic Wasting Disease, may pose a risk to human health. I believe this depends a lot on what types of shapes the deer and elk prion proteins can form.

3)Other disease-related amyloids

The techniques we developed to study the structure of PrPSc can also be applied to other disease-related misfolded proteins. In particular, we are interested in the structures of misfolded and aggregated conformers of α-synuclein, the microtubule-associated protein tau, the Alzheimer β-peptide, and many others. Comparing these structures with those of PrPSc will provide insights into the misfolding processes and how different primary structures influences higher level structural organization and aggregation.