Ronald Wetzel, Ph.D.

Professor, Department of Structural Biology, University of Pittsburgh School of Medicine; Member, Pittsburgh Institute for Neurodegenerative Diseases

Ron Wetzel received his BS from Drexel University and his PhD from the University of California, Berkeley. After postdoctoral experiences at the Max Planck Institute for Experimental Medicine, Goettingen, Germany, and at Yale University, he joined the fledgling biotechnology company Genentech in 1978. In 1989 he moved to SmithKline Beecham in King of Prussia, PA. In 1997 he took a position in the Graduate School of Medicine at the University of Tennessee in Knoxville. He moved to the University of Pittsburgh in 2006. His basic research has been funded by the Hereditary Disease Foundation, the Alzheimer’s Association, the American Health Assistance Foundation, and by the Institutes on Aging and on Neurodegenerative Disease and Stroke of the National Institutes of Health.

The Wetzel lab focuses on studies of amyloid fibrils and similar protein aggregates that have been implicated in neurodegenerative diseases such as Alzheimer’s, Huntington’s, and Parkinson’s diseases. The lab is currently concentrating on several questions, including: (a) understanding the mechanism of assembly of aggregates of the Alzheimer’s amyloid plaque peptide Aβ, and on the recently discovered ability of the same Aβ peptide to grow into amyloid fibrils of different structures, depending on growth conditions; (b) understanding the mechanism of assembly of polyglutamine sequences, important in Huntington’s disease, and on how amino acid sequences flanking the polyglutamine sequence in the disease protein modulate aggregation; (c) how the cellular environment affects aggregation pathways, and how aggregates affect cell behavior and viability. The biophysical part of the lab utilizes mass spectrometry, FTIR, CD, and fluorescence to study structure and assembly mechanisms.

Recent Publications:

  • Williams, A. D., Sega, M., Chen, M., Kheterpal, I., Geva, M., Berthelier, V., Kaleta, D. T., Cook, K.D. & Wetzel, R.  Structural properties of Aβ protofibrils stabilized by a small molecule.  Proc. Natl. Acad. Sci. USA 102: 7115-7120. 2005.
  • Bhattacharyya, A. M., Thakur, A. K. & Wetzel, R.  Polyglutamine aggregation nucleation: thermodynamics of a highly unfavorable protein folding reaction.  Proc. Natl. Acad. Sci. USA 102: 15,400-15,405. 2005.
  • Bhattacharyya, A. M., Thakur, A., Hermann, V., Thiagarajan, G., Willaims, A. D., Chellgren, B. W., Creamer, T. P. & Wetzel, R.  Oligoproline effects on polyglutamine conformation and aggregation.  J. Mol. Biol. 355: 524-535. 2006.
  • Williams, A. D. & Wetzel, R. Alanine scanning mutagenesis of Aβ(1-40) amyloid fibril stability.  J. Mol. Biol. 357: 1283-1294. 2006.
  • Kheterpal, I., Chen, M., Cook, K. D., & Wetzel, R.  Structural differences in Aβ amyloid protofibrils and fibrils mapped by hydrogen exchange – mass spectrometry with on-line proteolytic fragmentation. J. Mol. Biol.  361: 785-795. 2006.
  • Slepko, N., Bhattacharyya, A. M., Jackson, G. R., Steffan, J. S., Marsh, J. L., Thompson, L. M. & Wetzel, R.  Normal repeat length polyglutamine peptides accelerate aggregation nucleation and cytotoxicity of expanded polyglutamine proteins.  Proc. Natl. Acad. Sci. USA 103: 14367-14372. 2006.
  • Crick, S. L., Jayaraman, M., Frieden, C., Wetzel, R. & Pappu, R. V. Fluorescence correlation spectroscopy shows that monomeric polyglutamine molecules form collapsed structures in aqueous solutions.  Proc. Natl. Acad. Sci. USA 103: 16764-16769. 2006.
  • Gardberg, A. S., Dice, L. T., Ou, S., Rich, R. L., Helmbrecht, E., Ko, J., Wetzel, R., Myszka, D. G., Patterson, P. H., and Dealwis, C. Molecular basis for passive immunotherapy of Alzheimer’s disease.  Proc. Natl. Acad. Sci. USA 104: 15659-15664.  2007.
  • Wetzel, R., Shivaprasad, S. & Williams, A.D.  Plasticity in amyloid fibrils.  Biochem. 46: 1-10. 2007.
  • Kodali, R. & Wetzel, R.  Polymorphism in the intermediates and products of amyloid assembly.  Curr. Opin. Str. Biol. 17: 48-57. 2007.
  • Thakur, A. K., Jayaraman, M., Mishra, R., Thakur, M., Chellgren, V. M., Byeon, I.-J., Anjum, D. H., Kodali, R., Creamer, T. P., Conway, J. F., Gronenborn, A. M., & Wetzel, R., Polyglutamine disruption of the huntingtin exon1 N-terminus triggers a complex aggregation mechanism.  Nature Str. Mol. Biol. 16: 380-389. 2009.
  • Gu, X., Greiner, E.R, Mishra, R., Kodali, R., Osmand, A., Finkbeiner, S., Steffan, J.S., Thompson, L.M., Wetzel, R., & Yang, X.W., Serines 13 and 16 are critical determinants of full-length human mutant Huntingtin induced disease pathogenesis in HD mice. Neuron 64: 828-840. 2009. PMID: 20064390.
  • Kodali, R., Williams, A.D., Chemuru, S., & Wetzel, R., Ab(1-40) forms five distinct amyloid structures whose β-sheet contents and fibril stabilities correlate. J. Mol. Biol. 401: 503-517. 2010.
  • Kar, K., Jayaraman, M., Sahoo, B., Kodali, R, & Wetzel, R., Critical nucleus size for disease- related polyglutamine aggregation is repeat length dependent.  Nature Str. Mol. Biol. 18: 328-336. 2011.
  • Sivanandam, V.N., Jayaraman, M., Hoop, C.L., Kodali, R., Wetzel, R., & van der Wel, P.C.A., The aggregation-enhancing Huntingtin N-terminus is helical in amyloid fibrils.  J. Amer. Chem. Soc. 133: 4558-4566. 2011.