Ronald Wetzel Director, Amyloid and Neurodegenerative Diseases Research Laboratory Professor, Department of Medicine, Graduate School of Medicine http://gsm.utmck.edu/neuro/main.htm BS: Chemistry, Drexel University, 1969 PhD:Organic Chemistry, U. California, Berkeley, 1973 UT Medical Center 1924 Alcoa Hwy R221 Knoxville , TN 37920 865-544-9168 rwetzel@mc.utmck.edu

Keywords:
Amyloid, Alzheimer's Disease, Huntington's Disease, polyglutamine, neurodegeneration

Research Area:
Protein biochemistry and biophysics

Description of Research:
Protein aggregation into amyloid fibrils and other aggregates is a common theme in the molecular pathology of Alzheimer's disease, Parkinson's disease, Huntington's Disease, amyotrophic lateral sclerosis, and Creutzfeld-Jacob Disease and other prion diseases. My lab is interested in the structures, assembly mechanisms, and toxicity mechanisms of protein aggregation in neurodegenerative diseases.

In the Alzheimer's disease system, we are currently studying the mechanism by which globular proteins inhibit fibril formation in vitro. We are also studying the structures of Alzheimer's disesae-related amyloid fibrils and amyloid assembly intermediates using the technique of hydrogen-deuterium exchange, in collaboration with the labs of fellow GST facultry members Kelsey Cook (Chemistry) and Engin Serpersu (Biochemistry and Molecular and Cellular Biology). Another structural approach involves the use of certain novel monoclonal antibodies we have recently developed. We are also developing new diagnostic tools for identifying patients in early stages of AD.

Huntington's Disease and related genetic neurological disorders are caused by the expansion of CAG repeats in DNA leading to lengthening of polyglutamine sequences in certain proteins to sequences which, in ways which are not yet clear, cause neuronal cell loss and dysfunction. We have developed powerful new ways of studying polyglutamine sequences in vitro and are using these methods to investigate the structural basis of the polyglutamine length effect at the protein level. We are also using cell culture experiments to test certain hypotheses on the mechanism of polyglutamine toxicity. We are developing an assay for screening compounds for their abilities to inhibit polyglutamine aggregation, as well as an assay for detection of certain subtypes of polyglutamine aggregates in biological samples.

Selected Publications:

• Williams, A.D., M. Sega, M. Chen, I. Kheterpal, M. Geva, V. Berthelier, D.T. Kaleta, K.D. Cook and R. Wetzel (2005) "Structural properties of A ß protofibrils stabilized by a small molecule." PNAS. 102(20): 7115-7120.


• Whitttemore, N.A., R. Mishra, I. Kheterpal, A.D. Williams. R. Wetzel and E.H. Serpersu (2005) "Hydrogen-Deuterium (H/D) Exchange Mapping of Abeta (1)(-)(40) Amyloid Fibril Secondary Structure Using Nuclear Magnetic Resonance Spectroscopy." Biochemistry, 22;44(11): 4434-4441.


• Guo, J.T., R. Wetzel and Y. Xu (2004) "Molecular modeling of the core of Abeta amyloid fibrils." Proteins, 57(2): 357-64.


• Thakur, A.K., W. Yang and R. Wetzel (2004) "Inhibition of polyglutamine aggregate cytotoxicity by a structure-based elongation inhibitor." FASEB J. 18(7): 923-925.


• Venkatraman, P., R. Wetzel, M. Tanaka, N. Nukina and A.L. Goldberg (2004) "Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polygluatime-containing proteins." Mol. Cell. 14(1): 95-104.


• Cannon, M. J., A. D. Williams, R. Wetzel, and D. G. Myszka (2004) “Kinetic analysis of beta-amyloid fibril elongation.” Anal. Biochem. 328: 67-75.


• Wetzel, R. (2004) "Amyloid" Encyclopedia of Biological Chemistry, 1: 99-104.


• Shivaprasad, S. and R. Wetzel. (2004) "An Intersheet Packing Interaction in Aß Fibrils Mapped by Disulfide Cross-Linking." Biochemistry, 43: (49)15310-15317.


• O'Nuallain, B., A. Williams, P. Westermark and R. Wetzel (2004) "Seeding Specificity in Amyloid Growth Induced by Heterologous Fibrils." J. Biol. Chem. 279: 17490-17499


• Williams, A., E. Portelius, I. Kheterpal, J. Guo, K. Cook, Y. Xu and R. Wetzel (2004) "Mapping Aß Amyloid Fibril Secondary Structure Using Scanning Proline Mutagenesis." J. Mol. Biol. 335: 833-842.


• Kheterpal, I., H. Lashuel, D. Hartley, T. Walz, P. Lansbury, Jr. and R. Wetzel. (2003) "Aß Protofibrils Possess a Stable Core Structure Resistant to Hydrogen Exchange" Biochemistry, 42:14092-14098


• Kheterpal, I., R. Wetzel and K.D. Cook. (2003) "Enhanced correction methods for hydrogen exhange-mass spectrometric studies of amyloid fibrils" Prot. Sci. 12:635-643


• Thakar, A. and R. Wetzel. (2002) "Mutational analysis of the structural organization of polyglutamine aggregates" Proc. Natl. Acad. Sci. (USA) 99:17014-17019