Holger Wille

Area of Study / Keywords

prion amyloid protein-misfolding disease bovine spongiform encephalopathy prions genetic prions sporadic prions structure-based vaccines Alzheimer's disease Parkinson's disease

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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.

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Research

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., 2009a) 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.

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 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.

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).

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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. This course is not a substitute for required courses in Biochemistry. Requires consent of the Department.

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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.

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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.

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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.

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BIOCH 626B - Special Topics in Protein Research

Seminar course for advanced students. Detailed consideration is given to recent advances in research on protein structure and function and mechanism of enzyme action. Prerequisite: BIOCH 420 or consent of Department.

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Browse more courses taught by Holger Wille

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

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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

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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

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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

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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

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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

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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

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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

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Overduin M., Wille H., Westaway D.

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

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

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

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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

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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

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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

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

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