Progress in diagnosing and treating amyloid diseases has been hindered by lack of information on the structures, pathways of formation, and modes of toxicity of amyloid fibers and oligomers. In contrast to the increasingly successful attack on cancer, infectious, and metabolic diseases, treating amyloid diseases has proceeded in a near vacuum of knowledge about the structure and action of the etiologic agents. Amyloid diseases include not only Alzheimer's, which afflicts more than 5 million Americans today, but also Parkinson's, prion diseases, diabetes type II, senile systemic amyloidosis, light chain amyloidosis, and many more. All of these conditions are associated with elongated, unbranched protein fibers, 10-20nm in diameter, but in each disease the associated fiber is formed from a different protein. In the systemic amyloid diseases, fibers seem to be the etiologic agents;in the neurodegenerative amyloid diseases, small oligomers of the fiber-forming proteins are the causative agents. The overall goal of this project is to understand at the molecular level how amyloid fibers and oligomers form and kill cells. This knowledge will speed the design and testing of diagnostics and therapeutics for amyloid diseases. In previous work we determined structures of fibers and oligomers working with crystals that are 30,000 to 100,000 times smaller than the protein crystals normally used for structure determination. This has necessitated pioneering new methods of microcrystallography. With these new methods in the past grant period, we determined structures of some 90 amyloid fiber-like structures of segments of amyloid proteins that reveal the atomic level architecture of disease related fibers. Recently this approach has turned up two new types of structures that seem to explain prion aggregation and amyloid small oligomers. We will extend studies of these new types of structures, including of their pathways of formation and their biological toxicity. And by studying the structure of an amyloid oligomer in complex with an antibody that recognizes toxic oligomers of different proteins, we will identify the common features of toxic amyloid oligomers. As a start to designing chemical and biochemical interventions for amyloid disease, we have determined atomic structures for small molecules bound to amyloid segments. We have also designed two inhibitors of amyloid fiber growth. In the new grant period we will seek to understand the mechanisms of amyloid formation and toxicity. Because of the complexity of the scientific study of amyloid disease, we have developed a wide network of collaborators-local, national, and international--with whom we share information and methods.

Public Health Relevance

Amyloid diseases, including Alzheimer's, Parkinson's, diabetes type II, and the related Lou Gehrig's and Huntington's diseases, afflict millions of Americans. Our goal is to enable ways to slow or reverse these diseases by determining the mechanism of formation and toxicity of their causative agents. Using frontier methods, we learn the molecular properties of these agents, and the way they interact with potential biological and chemical inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG029430-07
Application #
8549044
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Petanceska, Suzana
Project Start
2007-09-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
7
Fiscal Year
2013
Total Cost
$341,846
Indirect Cost
$115,997
Name
University of California Los Angeles
Department
Genetics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Moshe, Asher; Landau, Meytal; Eisenberg, David (2016) Preparation of Crystalline Samples of Amyloid Fibrils and Oligomers. Methods Mol Biol 1345:201-10
Do, Thanh D; LaPointe, Nichole E; Nelson, Rebecca et al. (2016) Amyloid β-Protein C-Terminal Fragments: Formation of Cylindrins and β-Barrels. J Am Chem Soc 138:549-57
Soriaga, Angela B; Sangwan, Smriti; Macdonald, Ramsay et al. (2016) Crystal Structures of IAPP Amyloidogenic Segments Reveal a Novel Packing Motif of Out-of-Register Beta Sheets. J Phys Chem B 120:5810-6
Soragni, Alice; Janzen, Deanna M; Johnson, Lisa M et al. (2016) A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas. Cancer Cell 29:90-103
Colletier, Jacques-Philippe; Sawaya, Michael R; Gingery, Mari et al. (2016) De novo phasing with X-ray laser reveals mosquito larvicide BinAB structure. Nature 539:43-47
Sawaya, Michael R; Rodriguez, Jose; Cascio, Duilio et al. (2016) Ab initio structure determination from prion nanocrystals at atomic resolution by MicroED. Proc Natl Acad Sci U S A 113:11232-11236
Soragni, Alice; Yousefi, Shida; Stoeckle, Christina et al. (2015) Toxicity of eosinophil MBP is repressed by intracellular crystallization and promoted by extracellular aggregation. Mol Cell 57:1011-21
Kurt, Timothy D; Jiang, Lin; Fernández-Borges, Natalia et al. (2015) Human prion protein sequence elements impede cross-species chronic wasting disease transmission. J Clin Invest 125:1485-96
Saelices, Lorena; Johnson, Lisa M; Liang, Wilson Y et al. (2015) Uncovering the Mechanism of Aggregation of Human Transthyretin. J Biol Chem 290:28932-43
Rodriguez, Jose A; Ivanova, Magdalena I; Sawaya, Michael R et al. (2015) Structure of the toxic core of α-synuclein from invisible crystals. Nature 525:486-90

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