Holger Wille, Dr. rer. nat., Dipl. Biol.

Professor, Faculty of Medicine & Dentistry - Biochemistry Dept

Pronouns: he, him, his

Contact

Professor, Faculty of Medicine & Dentistry - Biochemistry Dept
Email
wille@ualberta.ca
Phone
(780) 248-1712
Address
1-10C Brain And Aging Research Building
8710 - 112 St NW
Edmonton AB
T6G 2M8

Overview

Area of Study / Keywords

prion amyloid protein-misfolding disease chronic wasting disease prions genetic prions sporadic prions structure-based vaccines Alzheimer's disease Parkinson's disease


About

The general focus of my work is the structure of amyloids and other disease-related, misfolded proteins. In particular, I am 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. The mechanistic similarities and their molecular underpinnings represent interesting research avenues beyond the classical prion diseases. The scope of my current experimental approaches is centered on electron microscopy, three-dimensional reconstruction approaches, X-ray fiber diffraction, and other biochemical and biophysical methods.


Research

Prion structure: 

The molecular structure of PrPSc has seen major progress in recent years. However, there is still some discussion in the prion field about some of the details. Our earlier investigations using X-ray fiber diffraction (Wille et al., 2009) indicated that the molecular architecture of PrPSc should be based on a four-rung β-solenoid structure. This finding contradicted most molecular models that were proposed prior to the cryo electron microscopy studies on the structure of PrPSc (reviewed in Wille & Requena, 2018). In other studies (Vázquez-Fernández et al., 2016; Kamali-Jamil et al., 2021) image processing allowed us to generate three-dimensional reconstructions of single PrPSc amyloid fibrils, which, again, were consistent with the hypothesis of a four-rung β-solenoid structure as the basic fold for the infectious prion.

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 amyloid-β peptide, and others. Comparing these structures with those we described for PrPSc provided insights into the misfolding process and how different primary structures may influence higher-level structural organization and aggregation.

Structural mimics: 

We are using a protein engineering approach to design and construct structural mimics for the structure of PrPSc and other misfolded proteins. By using innocuous proteins that are unrelated to mammalian proteins, we explored, among others, the four-rung β-solenoid fold we proposed for the structure of PrPSc and its properties without having to use biocontainment facilities. Additionally, these structural mimics allow us to manipulate and control the protein fold in ways that cannot be achieved with the mammalian proteins.

Rationally designed, structure-based vaccines: 

Based on our knowledge about the structure of PrPSc and of other pathogenic protein aggregates, we used innocuous protein scaffolds to engineer vaccine candidates that expose select surface residues to mimic the disease-causing conformers of the prion protein, α-synuclein, the amyloid-β peptide, and the microtubule-associated protein tau. In a first set of experiments targeting PrPSc, immunization of wild-type mice resulted in an immune response that was specific for PrPSconly, and did not recognize linear epitopes or natively folded PrP. Similar experiments to test the specificity of vaccine candidates for the disease-associated conformations of other misfolded proteins (α-synuclein, amyloid-β peptide, tau protein) are well underway and have yielded very promising results. Efficacy trials for the prion vaccine candidates in transgenic mice modeling genetic prion diseases have resulted in substantial extensions of disease-free survival, which constitutes a major breakthrough. A manuscript describing this novel, structure-based prion vaccine approach has been submitted for publication (Fang et al., 2025). Furthermore, two papers describing the design and in vivo efficacy of α-synuclein-based vaccine candidates in a transgenic mouse model were recently published (Flores-Fernandez et al., 2024; Pesch et al., 2024). A third manuscript on the α-synuclein-based vaccine candidates has been submitted for publication recently (Ma et al., 2025). This work also resulted in a patent application that was originally filed in 2019 (Wille et al., 2024) and is pending in Canada, the EU, as well as Hong Kong, and Japan. The U.S. patent has been issued in 2024 and will be in effect until 2040.

Solenoid Biosciences LLC:

The invention of structure-based vaccines targeting neurodegenerative diseases formed the basis for a spin-off company that was founded in February 2025. The company will focus on commercializing the vaccines targeting Alzheimer’s disease and Parkinson’s disease and is currently in its formation and initial fund-raising phase.

Courses

BIOCH 420 - Proteins: Structure, Function, and Regulation

Principles of protein structure, function, and dynamics, with an introduction to force fields used in modern molecular dynamics. Focus topics include an introduction to intrinsically disordered proteins and their role in misfolding diseases, the structural biology, ligand binding, and mechanisms of membrane bound enzymes, and mechanisms underlying the regulation of protein function and enzymes involved in cell signaling. Prerequisites: BIOCH 320, with a minimum grade of B- or consent of Department. This course is intended for students in Honors or Specialization in Biochemistry. Students in other programs may be admitted subject to availability and with the consent of the Department. Graduate students may not register for credit (see BIOCH 520).


BIOCH 498 - Directed Research Project

Supervised research within a laboratory in the Department of Biochemistry, to be carried out over one term (Fall or Winter). The results of the research project will be presented in a short seminar. This course is intended for senior students in Honors or Specialization in Biochemistry. Students in other programs may be admitted subject to availability and background. Prerequisites: BIOCH 310, 320 and 330, all with a minimum grade of B-. This course is not a substitute for required courses in Biochemistry. Requires consent of the Department.


BIOCH 499A - Directed Research Project

Supervised research within a laboratory in the Department of Biochemistry, to be carried out over both terms of Fall/Winter. The results of the research project will be presented in a final written report and an oral presentation. This course is required for the Honors program, but can be taken as a science elective by students in the Specialization program. Students in other programs may be admitted subject to availability. Prerequisites: BIOCH 401 and consent of the Department.


BIOCH 499B - Directed Research Project

Supervised research within a laboratory in the Department of Biochemistry, to be carried out over both terms of Fall/Winter. The results of the research project will be presented in a final written report and an oral presentation. This course is required for the Honors program, but can be taken as a science elective by students in the Specialization program. Students in other programs may be admitted subject to availability. Prerequisites: BIOCH 401 and consent of the Department.


BIOCH 520 - Protein Chemistry, Structure, and Function

Principles of protein structure, function, and dynamics, with an introduction to force fields used in modern molecular dynamics. Focus topics include an introduction to intrinsically disordered proteins and their role in misfolding diseases, the structural biology, ligand binding, and mechanisms of membrane bound enzymes, and mechanisms underlying the regulation of protein function and enzymes involved in cell signaling. Prerequisites: BIOCH 320, with a minimum grade of B- or consent of Department. Lectures are the same as for BIOCH 420, but with additional assignments and evaluation appropriate to graduate studies. Students in other programs may be admitted subject to availability and with the consent of the Department This course may not be taken for credit if credit has already been obtained in BIOCH 420.


BIOCH 620 - Selected Topics in Protein Structure, Function, and Regulation

Directed reading and seminar course, based on papers taken from recent literature of protein research. Students critically discuss the papers and give oral presentations to the class. Designed for graduate students. Prerequisite: BIOCH 420 or equivalent, or consent of Department.


BIOCH 665A - Special Topics in Protein Folding and Prion Diseases

Seminar course for advanced students focused on recent advances in research into mechanisms of protein folding and disease states caused by protein misfolding, including prion diseases. Prerequisite: BIOCH 520 or consent of the Department.


BIOCH 665B - Special Topics in Protein Folding and Prion Diseases

Seminar course for advanced students focused on recent advances in research into mechanisms of protein folding and disease states caused by protein misfolding, including prion diseases. Prerequisite: BIOCH 520 or consent of the Department.


Browse more courses taught by Holger Wille

Featured Publications

Michael Overduin, Gestél C. Kuyler, Mansoore Esmaili, Catharine A. Trieber, Claudia Acevedo-Morantes, Alexander P. Orazietti, Rustem Shaykhutdinov, Rakesh K. Bhat, Tomisin Omotoso, Sabiha Tajammul, Mohammad Rahim, Sophie Zinn-Justin, Russell E. Bishop, R. Scott Prosser, Holger Wille, Bert Klumperman

Biophysical Chemistry. 2025 October; 10.1016/j.bpc.2025.107489


Pallabi Paul, Mallesh Rathnam, Aria Khalili, Leonardo Cortez, Mahalashmi Srinivasan, Emmanuel Planel, Jae-Young Cho, Holger Wille, Valerie Sim, Sue-Ann Mok, Satyabrata Kar

International Journal of Nanomedicine. 2025 February; 10.2147/IJN.S494104


Jose Miguel Flores‐Fernandez, Verena Pesch, Aishwarya Sriraman, Enrique Chimal‐Juarez, Sara Amidian, Xiongyao Wang, Caleb Duckering, Andrew Fang, Sara Reithofer, Liang Ma, Leonardo M. Cortez, Valerie L. Sim, Gültekin Tamgüney, Holger Wille

Bioengineering & Translational Medicine. 2024 April; 10.1002/btm2.10665


Dane Marijan, Evgenia A. Momchilova, Daniel Burns, Sahil Chandhok, Richard Zapf, Holger Wille, Davit A. Potoyan, Timothy E. Audas

Nature Communications. 2024 February; 10.1038/s41467-024-45536-0


Brain. 2024 January; 10.1093/BRAIN/AWAE061


Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 2024 January; 10.1016/J.SAA.2023.123817


Scientific Reports. 2024 January; 10.1038/S41598-023-50465-X


M. Carmen Garza, Sang-Gyun Kang, Chiye Kim, Eva Monleón, Jacques van der Merwe, David A. Kramer, Richard Fahlman, Valerie L. Sim, Judd Aiken, Debbie McKenzie, Leonardo M. Cortez, Holger Wille

International Journal of Molecular Sciences. 2023 December; 10.3390/ijms242417525


Sheng Chun Chang, Samia Hannaoui, Maria Immaculata Arifin, Yuan-Hung Huang, Xinli Tang, Holger Wille, Sabine Gilch

Communications Biology. 2023 November; 10.1038/s42003-023-05541-3


Jose Miguel Flores-Fernandez, Verena Pesch, Aishwarya Sriraman, Enrique Chimal-Juarez, Sara Amidian, Xiongyao Wang, Sara Reithofer, Liang Ma, Gültekin Tamgüney, Holger Wille

2023 June; 10.1101/2023.06.30.547254


Scientific Reports. 2023 January; 10.1038/S41598-023-29559-Z


Annals of the New York Academy of Sciences. 2023 January; 10.1111/NYAS.14975


Min Wu, Holger Wille, Maria Stepanova

The Journal of Chemical Physics. 2022 December; 10.1063/5.0116032


Paul P.S., Cho J.Y., Wu Q., Karthivashan G., Grabovac E., Wille H., Kulka M., Kar S.

JOURNAL OF NANOBIOTECHNOLOGY. 2022 December; 20 (1) 10.1186/s12951-022-01269-0


Anand, B, Wu, Q, Nakhaei-Nejad, M, Karthivashan, G, Dorosh, L, Amidian, S, Dahal, A, Li, X, Stepanova, M, Wille, H, Giuliani, F, Kar, S

Bioactive Materials. 2022 November; 17 https://doi.org/10.1016/j.bioactmat.2022.05.030


Bibin Anand, Qi Wu, Maryam Nakhaei-Nejad, Govindarajan Karthivashan, Lyudmyla Dorosh, Sara Amidian, Abhishek Dahal, Xiuju Li, Maria Stepanova, Holger Wille, Fabrizio Giuliani, Satyabrata Kar

Bioactive Materials. 2022 November; 10.1016/j.bioactmat.2022.05.030


Daude N., Lau A., Vanni I., Kang S.G., Castle A.R., Wohlgemuth S., Dorosh L., Wille H., Stepanova M., Westaway D.

JOURNAL OF BIOLOGICAL CHEMISTRY. 2022 April; 298 (4) 10.1016/j.jbc.2022.101770


Journal of Biological Chemistry. 2022 January; 10.1016/J.JBC.2022.101770


Journal of Nanobiotechnology. 2022 January; 10.1186/S12951-022-01269-0


Anand B.G., Wu Q., Karthivashan G., Shejale K.P., Amidian S., Wille H., Kar S.

Bioactive Materials. 2021 December; 6 (12):4491-4505 10.1016/j.bioactmat.2021.04.029


Bibin G. Anand, Qi Wu, Govindarajan Karthivashan, Kiran P. Shejale, Sara Amidian, Holger Wille, Satyabrata Kar

Bioactive Materials. 2021 December; 10.1016/j.bioactmat.2021.04.029


Eduardo Padilla-Camberos, Ivan Moises Sanchez-Hernandez, Omar Ricardo Torres-Gonzalez, Patricia Ramirez-Rodriguez, Emmanuel Diaz, Holger Wille, Jose Miguel Flores-Fernandez

Materials. 2021 August; 10.3390/ma14164543


Padilla-Camberos E., Sanchez-Hernandez I.M., Torres-Gonzalez O.R., Ramirez-Rodriguez P., Diaz E., Wille H., Flores-Fernandez J.M.

Materials. 2021 August; 14 (16) 10.3390/ma14164543


Samia Hannaoui, Elizabeth Triscott, Camilo Duque Velásquez, Sheng Chun Chang, Maria Immaculata Arifin, Irina Zemlyankina, Xinli Tang, Trent Bollinger, Holger Wille, Debbie McKenzie, Sabine Gilch

PLOS Pathogens. 2021 July; 10.1371/journal.ppat.1009795


Hannaoui S., Triscott E., Velásquez C.D., Chang S.C., Arifin M.I., Zemlyankina I., Tang X., Bollinger T., Wille H., McKenzie D., Gilch S.

PLoS Pathogens. 2021 July; 17 (7) 10.1371/journal.ppat.1009795


Leonardo M. Cortez, Satish K. Nemani, Camilo Duque Velásquez, Aishwarya Sriraman, YongLiang Wang, Holger Wille, Debbie McKenzie, Valerie L. Sim

PLOS Pathogens. 2021 June; 10.1371/journal.ppat.1009703


Kamali-Jamil R., Ester Vázquez-Fernández, Tancowny B., Rathod V., Amidian S., Wang X., Tang X., Fang A., Senatore A., Hornemann S., Dudas S., Aguzzi A., Young H.S., Wille H.

PLoS Pathogens. 2021 June; 17 (6) 10.1371/journal.ppat.1009628


Cortez L.M., Nemani S.K., Velásquez C.D., Sriraman A., Wang Y.L., Wille H., McKenzie D., Sim V.L.

PLoS Pathogens. 2021 June; 17 (6) 10.1371/journal.ppat.1009703


Michael Overduin, Holger Wille, David Westaway

Chemistry and Physics of Lipids. 2021 May; 10.1016/j.chemphyslip.2021.105063


Overduin M., Wille H., Westaway D.

CHEMISTRY AND PHYSICS OF LIPIDS. 2021 May; 236 10.1016/j.chemphyslip.2021.105063


Min Wu, Lyudmyla Dorosh, Gerold Schmitt-Ulms, Holger Wille, Maria Stepanova

PLOS Computational Biology. 2021 March; 10.1371/journal.pcbi.1008771


Wu M., Dorosh L., Schmitt-Ulms G., Wille H., Stepanova M.

PLoS Computational Biology. 2021 March; 17 (3) 10.1371/journal.pcbi.1008771


Hadeel Alyenbaawi, Richard Kanyo, Laszlo F Locskai, Razieh Kamali-Jamil, Michèle G DuVal, Qing Bai, Holger Wille, Edward A Burton, W Ted Allison

eLife. 2021 February; 10.7554/eLife.58744


Alyenbaawi H., Kanyo R., Locskai L.F., Kamali-Jamil R., Duval M.G., Bai Q., Wille H., Burton E.A., Ted Allison W.

eLife. 2021 February; 10 10.7554/eLife.58744


Disease Models & Mechanisms. 2021 January; 10.1242/DMM.048929


PLOS Pathogens. 2021 January; 10.1371/JOURNAL.PPAT.1009628


Ghaffari Sharaf M., Amidian S., Rathod V., Crichton A., Damji K.F., Wille H., Unsworth L.D.

Scientific Reports. 2020 December; 10 (1) 10.1038/s41598-020-72737-6


Minikel E.V., Zhao H.T., Le J., O'Moore J., Pitstick R., Graffam S., Carlson G.A., Kavanaugh M.P., Kriz J., Kim J.B., Ma J., Wille H., Aiken J., McKenzie D., Doh-Ura K., Beck M., O'Keefe R., Stathopoulos J., Caron T., Schreiber S.L., Carroll J.B., Kordasiewicz H.B., Cabin D.E., Vallabh S.M.

NUCLEIC ACIDS RESEARCH. 2020 November; 48 (19):10615-10631 10.1093/nar/gkaa616


Esmaili M., Acevedo-Morantes C., Wille H., Overduin M.

BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES. 2020 September; 1862 (10) 10.1016/j.bbamem.2020.183360


View additional publications