Unlocking the Mysteries of Amyloid Diseases with Macrocyclic β-Sheet Peptides
James Nowick
Professor and Department Chair, University of California, Irvine, Department of Chemistry
Amyloid oligomers have emerged as the key toxic species in amyloid diseases. Our laboratory is determining the structures and mechanism of action of oligomers of peptides and proteins associated with Alzheimer's disease, Parkinson's disease, frontotemporal dementias, type II diabetes, and other diseases involving protein aggregation. We are able to obtain high-resolution structures by constraining fragments of the peptides and proteins to β-hairpins and determining the structures of the oligomers that form by X-ray crystallography. Through these studies, in conjunction with biophysical and cell biology experiments, we are gaining new insights into the molecular basis of amyloid diseases.
Alzheimer's disease has been a major focus of our efforts. The 40-42 amino acid peptide Aβ aggregates to form fibrils and toxic oligomers. While the fibrils and the resulting plaques are the visible hallmark of the disease, the soluble oligomers are now thought to be the damaging species responsible for neurodegeneration. By constraining peptides derived from Aβ to a β-hairpin conformation and preventing fibril formation by N-methylation, we have discovered that triangular trimers constitute a fundamental building block of amyloid oligomers. Through X-ray crystallography, we have elucidated high-resolution structures of the trimers, as well as the hexamers, dodecamers, and annular pores that the trimers form. We are now beginning to correlate the biophysical and biological properties these oligomers with those formed by full-length Aβ. This talk will describe our ongoing studies.
James Nowick is a Professor of Chemistry at the University of California, Irvine. He received his A.B. (Bachelors) degree in Chemistry in 1985 from Columbia University and his Ph.D. degree in Organic Chemistry in 1990 from MIT, where he was both an NSF Graduate Fellow and an ACS Division of Organic Chemistry Graduate Fellow. After an NSF postdoctoral fellowship in supramolecular chemistry at MIT, he began his independent career as an Assistant Professor at UCI in 1991. He was promoted to Associate Professor in 1996 and Professor in 1998. He is currently Chair of the Department of Chemistry.
Dr. Nowick's research interests include peptidomimetic chemistry, molecular recognition, and supramolecular chemistry, with a central focus on understanding how peptides fold and interact. In recognition of his scientific contributions, he has received a Camille and Henry Dreyfus Foundation New Faculty Award, an American Cancer Society Junior Faculty Research Award, an NSF Young Investigator Award, an Arnold and Mabel Beckman Foundation Young Investigator Award, a Presidential Faculty Fellow Award, a Camille Dreyfus Teacher-Scholar Award, an Alfred P. Sloan Research Fellowship, and an American Chemical Society Arthur C. Cope Scholar Award. He is a Fellow of the American Association for the Advancement of Science and a Fellow of the American Chemical Society. For his contributions to research and education at UCI, he has received the Award for Outstanding Faculty Contribution to Undergraduate Research, the Chancellor's Award for Excellence in Undergraduate Research, and the School of Physical Sciences Award for Outstanding Contributions to Undergraduate Education.