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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: Director, Centre for Prions and Protein Folding Diseases

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

E-mail: wille@ualberta.ca

Background

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 (PrP^Sc) 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 º£½ÇÉçÇø and from other universities and research institutions nationally and internationally.

Current Research

Prion Structure

The molecular structure of PrP^Sc 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 PrP^Sc is based on a four-rung β-solenoid structure. This finding contradicted most molecular models that were proposed for the structure of PrP^Sc. In our most recent study (Vázquez-Fernández et al., 2016), we used electron cryomicroscopy to visualize individual PrP^Sc amyloid fibrils. Image processing allowed us to generate three-dimensional reconstructions of single PrP^Sc 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.

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.

Other Disease-related Amyloids

The techniques we developed to study the structure of PrP^Sc 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 PrP^Sc will provide insights into the misfolding processes and how different primary structures influences higher level structural organization and aggregation.

Selected Publications

Prion publications:
Chang, SC, Hannaoui, S, Arifin, MI, Huang, Y-H, Tang, X, Wille, H, Gilch, S (2023). Propagation of PrPSc in mice reveals impact of aggregate composition on prion disease pathogenesis. Communications Biology, 6, 1162.

Garza, MC, Kang, SG, Kim, C, Monleón, E, van der Merwe, J, Kramer, DA, Fahlman, R, Sim, V, Aiken, J, McKenzie, D, Cortez, LM, Wille, H (2023). In vitro and in vivo evidence towards fibronectin's protective effects against prion infection. International Journal of Molecular Sciences, 24, 17525.

Wu, M, Flores-Fernandez, JM, Wang, YL, Wille, H, Stepanova, M (2024). SERS Probing of Fungal HET-s Fibrils Formed at Neutral and Acidic pH Conditions. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 309, 123817.

Alzheimer's disease publications:
Williams, D, Yan, BQ, Wang, H, Negm, L, Sackmann, C, Verkuyl, C, Rezai-Stevens, V, Eid, S, Sato, C, Vediya, N, Watts, JC, Wille, H, Schmitt-Ulms, G (2023). Somatostatin slows Aβ amyloid plaque deposition in aged APPNL-F/NL-F mice by blocking early Aβ aggregation. Scientific Reports, 13, 2337.

Paul, PS, Patel, T, Cho, JY, Yarahmady, A, Khalili, A, Semenchenko, V, Wille, H, Kulka, M, Mok, SA, Kar, S (2024). Native PLGA nanoparticles attenuate Aβ-seed induced tau aggregation under in vitro conditions: potential implication in Alzheimer's disease pathology. Scientific Reports, 14, 144.

Paul, PS, Rathnam, M, Khalili, A, Cortez, L, Srinivasan, M, Planel, E, Cho, J-Y, Wille, H, Sim, V, Mok, S-A, Kar, S (2025). Temperature-dependent aggregation of tau protein is attenuated by native PLGA nanoparticles under in vitro conditions. International Journal of Nanomedicine, 20, 1999-2019.

Parkinson's disease publications:
Flores-Fernandez, JM, Pesch, V, Sriraman, A, Chimal-Juarez, E, Amidian, S, Wang, X, Duckering, C, Fang, A, Reithofer, S, Ma, L, Cortez, LM, Sim, VL, Tamgüney, G & Wille, H (2024). Rational design of structure-based vaccines targeting misfolded alpha-synuclein conformers of Parkinson’s disease and related disorders. Bioengineering & Translational Medicine, 9, e10665.

Pesch, V, Flores-Fernandez, JM, Reithofer, S, Ma, L, Özdüzenciler, P, Busch, Y, Sriraman, A, Wang, YL, Amidian, S, Kroepel, CVM, Müller, L, Lien, Y, Rudtke, O, Frieg, B, Schröder, GF, Wille, H, and Tamgüney, G (2024). Vaccination with structurally adapted fungal protein fibrils induces immunity to Parkinson’s disease. Brain, 147, 1644-1652.

Miscellaneous publications:
Cable, J, Graham, BS, Koup, RA, Seder, RA, Karikó, K, Pardi, N, Barouch, DH, Sharma, B, Rauch, S, Nachbagauer, R, Forsell, MNE, Schotsaert, M, Ellebedy, AH, Loré, K, Irvine, DJ, Pilkington, E, Tahtinen, S, Thompson, EA, Feraoun, Y, King, NP, Saunders, K, Alter, G, Moin, SM, Sliepen, K, Karlsson Hedestam, GB, Wardemann, H, Pulendran, B, Doria-Rose, NA, He, W-T, Juno, JA, Ataca, S, Wheatley, AK, McLellan JS, Walker, LM, Lederhofer, J, Lindesmith, LC, Wille, H, Hotez, PJ, Bekker, L-G (2023). Progress in vaccine development for infectious diseases — a Keystone Symposia report. Annals New York Academy of Sciences 1524, 65-86.

Marijan, D, Momchilova, EA, Burns, D, Chandhok, S, Zapf, R, Wille, H, Potoyan, DA, Audas, TE (2024). Protein thermal sensing regulates physiological amyloid aggregation. Nature Communications, 15, 1222.

Overduin, M, Kuyler, GC, Esmaili, M, Trieber, CA, Acevedo-Morantes, C, Orazietti, AP, Shaykhutdinov, R, Bhat, RK, Omotoso, T, Tajammul, S, Rahim, M, Zinn-Justin, S, Bishop, RE, Prosser, RS, Wille, H, Klumperman, B (2025). Design of zwitterionic fluorescent polymers for membrane protein solubilization in native nanodiscs. Biophysical Chemistry, 325, 107489.