Ronald B. Wetzel, Ph.D.
Professor, Structural Biology- Ph.D. Drexel University (1969)
- Office: 2046 Biomedical Science Tower-3
- Telephone:412-383-5271
- Fax:412-648-9008
- E-mail: rwetzel@pitt.edu
- Website:
Assembly, structure and cytotoxicity of pathological protein aggregates associated with neurodegenerative diseases.
Research Summary:
Many forms of neurodegenerative disease, including Alzheimer’s, Huntington’s, Parkinson’s, ALS, and various prion-related diseases, are associated with the appearance of protein aggregates in brain tissue. In fact, protein misfolding and aggregation occur routinely in healthy cells, but when these are accelerated by mutations or other factors they can lead to a cellular burden of aggregates that cannot be easily managed by the normal mechanisms. In most of these systems, the molecular mechanisms of aggregation are complex, involving a progression through different aggregate structures of potentially differing toxicities. The cellular environment, including the operation of the normal cellular mechanisms for dealing with misfolding, can modify the process. Dr. Wetzel's group focuses on studies of the Aß peptide that is the main protein component of the amyloid plaques found in Alzheimer’s disease, and on the protein huntingtin, the polyglutamine-containing protein that contains the Huntington’s disease mutation and that is found in intracellular aggregates in disease tissue. Their long-term goals are to understand the intrinsic molecular factors and extrinsic cellular factors that contribute to the assembly mechanisms and structures of various aggregates, and how the aggregates favored in the biological environment produce their toxic, neurodegenerative effects. Techniques include hydrogen exchange-mass spectrometry, and circular dichroism, fluorescence, and Fourier transform infrared spectroscopies. Cell culture methods focus on detection by a variety of fluorescence microscopy techniques.
Selected Publications:
Yang, W., Dunlap, J. R., Andrews, R. B. and Wetzel, R. Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells. Hum. Mol. Genet. 11: 2905-2917, 2002.
Williams, A.D., Portelius, E., Kheterpal, I., Guo, J.-T., Cook, K. D., Xu, Y. and Wetzel, R. Mapping Aß amyloid fibril secondary structure using scanning proline mutagenesis. J. Mol. Biol. 335: 833-842, 2004.
Bhattacharyya, A. M., Thakur, A. K. and Wetzel, R. Polyglutamine aggregation nucleation: thermodynamics of a highly unfavorable protein folding reaction. Proc. Natl. Acad. Sci. USA 102: 15,400-15,405, 2005.
Kheterpal, I., Chen, M., Cook, K. D. and Wetzel, R. Structural differences in Aß amyloid protofibrils and fibrils mapped by hydrogen exchange – mass spectrometry with on-line proteolytic fragmentation. J. Mol. Biol. 361: 785-795, 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.