Professor David S. Eisenberg

Professor David S. Eisenberg

Principal Investigator

david@mbi.ucla.edu
(tel) 310-825-3754
(fax) 310-206-3914
201A Boyer Hall

Administrative Assistant, Cindy Chau
cchau@mbi.ucla.edu
201 Boyer Hall

Mailing address:
Dept. Chemistry and Biochemistry
Univ. of Calif. Los Angeles
611 Charles Young Dr. East
Los Angeles, CA 90095-1569

Nicole Wheatley

Nicole Wheatley

PostDoc

The tumor suppressor protein p53, also known as “The Guardian of the Genome”, is the most commonly mutated protein in cancer. In addition to genetic mutations, p53 can become inactivated by misfolding and aggregation. Although certain genetic mutations promote p53 aggregation, wild type p53 as well is found in aggregated inclusions in certain cancer cells. My project aims to identify the mechanisms of p53 misfolding and aggregation. Questions that I address are the following: What cellular factors influence p53 aggregation? Do some p53 aggregates behave as amyloid, similar to proteins associated with neurodegenerative diseases? How do p53 reactivation drugs, such as ReAcP53, eliminate aggregates and restore native p53 function? To answer these questions, I use confocal microscopy on human cell lines expressing fluorescent-labeled p53 isoforms and mutants.

Paul Seidler

Paul Seidler

PostDoc

I am working on determining structures of Tau oligomers and amyloid fibers that are involved in Alzheimer’s disease and other tauopathies. Through these studies I hope to uncover the structural basis of toxicity and seeding, as well as to understand how certain Tau structures might protect against disease. Additionally I am working with Lin Jiang to develop inhibitors that block Tau fibrillization based on structures that our group has solved.

Lorena Saelices

Lorena Saelices

PostDoc

My professional goal is to contribute to the understanding of the molecular basis of amyloid-related diseases from a structural point of view, in order to design effective and safe potential peptide therapeutics. Recent studies in collaboration with the Department of Chemistry and Applied Bioscience at ETH Zürich have resulted in the design and assessment of successful peptide inhibitors of protein aggregation for Alzheimer’s disease and transthyretin amyloidosis. For my research, I combine structural analysis of amyloid protein segments and intact proteins with molecular and cell biology to test toxicity inhibition of our designs.

Boris Brumshtein

Boris Brumshtein

PostDoc

As a postdoctoral researcher at UCLA, I am in charge of planning and executing a fundamental science research program to understand biochemical processes of systemic amyloidosis disease, and build a foundation for development of a possible cure of the disease in future. Amyloidosis develops due to assembly of light-chain immunoglobulins into a protein polymer, known as amyloid fibrils. These fibrils possess a special biochemical properties preventing their clearance from the body, eventually leading to essential organs failure and death.
Recent research had shown that propagation of amyloid fibrils is mediated by a discrete, naturally occurring short peptide segments with a high propensity to assemble into insoluble beta-sheet structures. With a goal of illuminating the structural basis of systemic amyloidosis, I hypothesized that such peptide segments exist in immunoglobulin light-chains. In concordance with this hypothesis, I identified several peptide segments within lambda type immunoglobulins that induce formation of amyloid-like structures. Currently, I use a site-directed mutagenesis methods to assess the structural necessity of these peptide segments to light-chain immunoglobulin amyloidogenic potential, in hope to use this data for development of molecules that will disrupt amyloid formation, which is the ultimate long term goal of our research.

Qin Cao

Qin Cao

PostDoc

I am a postdoc in Eisenberg’s lab and my research here mostly focuses on the interaction between Amyloid beta (Aβ) and its binders (binding proteins/small molecules). My goal is to solve the crystal structure of binder stabilized Aβ (or Aβ derived peptides), or developing Aβ inhibitors from these binding protein/small molecules.

Shruti Sahay

Shruti Sahay

PostDoc

My research focuses on determining high-resolution structure of alpha-synuclein amyloid fibers that are involved in Parkinson’s disease pathology. I am trying to characterize the structure, seeding ability and toxic properties of alpha-synuclein fibers prepared by seeding recombinant alpha-synuclein with Parkinson’s disease brain extracts. Additionally, in collaboration with Prof. Massoud Akhtari at UCLA, I am also working on developing magnetic resonance imaging contrast agents for specifically detecting alpha-synuclein pathology in Parkinson’s disease brain.

Graduate Students

Sarah Griner

Sarah Griner

Graduate Student

My research focuses on determining the molecular structures of Amyloid Beta (Aβ), the protein responsible for Alzheimer’s Disease. Aβ is observed as multiple aggregated structures including amyloid fibrils, smaller protofibrils, as well as oligomeric species which are associated with higher toxicities. By determining the structures of the distinct species, I hope to identify what features are responsible for Aβ toxicity. To this end, I have focused on familial mutations in Aβ which alter the structure and contribute to heightened toxicity and early onset of the disease.

Michael Hughes

Michael Hughes

Graduate Student

Amyloid proteins are traditionally associated with neurodegenerative diseases like Alzheimer’s Disease, Parkinson’s Disease, and ALS. A hallmark of pathology from these neurodegenerative diseases is the presence of extraordinarily stable amyloid fibrils. Recently the McKnight lab has indicated that many RNA binding proteins with Low-Complexity (LC) domains such as FUS, TDP43, and hnRNPA2 can form a hydrogel composed of amyloid-like fibrils. LC domain oligomerization into fibrils is linked to important cellular functions; specifically stress granule formation. Unlike amyloid fibrils from neurodegenerative diseases, these hydrogel-forming amyloid fibrils are more labile. I study structure of segments from LC domains thought to be important for their fibril formation to identify structural features that may mediate their inherent lability relative to other amyloid fibrils.

Elizabeth Guenther

Elizabeth Guenther

Graduate Student

My research focuses on understanding the aggregation of TAR DNA Binding Protein 43, TDP-43, an amyloid protein implicated in Amyotrophic Lateral Sclerosis and other neurodegenerative diseases. I am interested in understanding how TDP-43 can form reversible aggregates in the form of stress granules as well as irreversible aggregates in the form of pathological deposits of diseases. I utilize a number of different techniques including X-ray crystallography, electron microscopy, SDS sensitivity assays, cellular toxicity assays and antibody binding to understand the fragments that are important for aggregation. Additionally, I have collaborated on a number of other projects in our lab including work on the proteins alpha-synuclein and SOD-1.

David Boyer

David Boyer

Graduate Student

I am using cryo-electron microscopy and diffraction techniques, along with X-ray crystallography, to study new and exciting structures of amyloid proteins. My main focus is discovering new structures of tau protein, which is involved in over 26 neurodegenerative diseases. These structures serve both to reveal fundamental insights of tau biochemistry and as templates for structure-based drug design. The overall goal is to develop structure-based inhibitors of tau aggregation that can be used to probe its role in neurodegenerative diseases and, hopefully, to prevent, delay, or reverse disease progression.

Jeannette Bowler

Jeannette Bowler

Graduate Student

My research focuses on characterizing the structure and mechanisms of cytotoxicity of α-synuclein, the protein implicated in Parkinson’s disease. I am particularly interested in the interaction of α-synuclein with lipids, as it has been suggested that membrane disruption by α-synuclein oligomers or fibrils may be one mechanism of cytotoxicity. In addition, I am working on determining structures of amyloidogenic segments from the polyglutamine-rich proteins Huntingtin and CPEB.

Xiaofei Lin

Xiaofei Lin

Graduate Student

Although the defining feature of amyloid-related diseases is their association with fibrils, studies from many laboratories have suggested that the toxic molecular agents are lower-molecular-weight entities of the same proteins, termed amyloid oligomers, that appear during the conversion of monomers to stable fibrils. Attempts to characterize the structures of amyloid oligomers have been hindered by their ensemble of shapes and stoichiometries, and their tendency to convert rapidly into fibrils. Recently, our lab has proposed that residues 28-38 of superoxide dismutase 1 (SOD1), a protein implicated in ALS, forms such a toxic oligomeric structure. Based on its crystal structure composed of a twisted β-sheet built of antiparallel, out-of-register β-strands, this oligomer has been termed ‘corkscrew.’ My research aims to computationally search the human proteome for new protein sequences capable of accommodating the ‘corkscrew’ toxic oligomer structure to shed light into the range of proteins capable of causing amyloid disease. My goal is to develop an accurate high throughput toxic amyloid oligomer prediction algorithm to ultimately aid in the development of therapeutics.

Kevin Murray

Kevin Murray

Graduate Student

Research Staff

Michael Sawaya

Michael Sawaya

Staff Scientist/Teacher

I help people to determine and analyze interesting macromolecular structures by crystallography. I assist with data collection, data processing, phasing, model building and structure interpretation, and teach others about these techniques.

Dan Anderson

Dan Anderson

Laboratory Manager/Research Scientist

As Laboratory Manager, my job fluctuates. I keep the lab running, at the level of ordering supplies, equipment, and performing or ordering repairs. I do some of the equipment training. I am Safety Representative for the Eisenberg lab. When I can, I lend technical advice for lab work and occasionally for crystallography.

Duilio Cascio

Duilio Cascio

Staff Scientist

There is a basic need to understand how proteins are involved in both normal and abnormal cellular processes. To understand how these proteins function at the molecular level, the detailed atomic structure is needed. The knowledge of the three-dimensional structures of proteins provides information upon which we can initiate new molecular, biological, biochemical, protein engineering and drug design efforts. My long-term goal is to provide state-of-the-art resources to researchers in the laboratory, enabling the detailed 3-D analysis of biological macromolecules that play essential roles in human health. I train students and postdocs to use sophisticated equipment and technologies. I also offer advice and technical assistance in sample preparation, crystallization, data collection, processing, atomic refinement and modelling.

Interns

Sam Abramowitz

Sam Abramowitz

Intern

samabramowitz@yahoo.com
Boston University Class of 2014, BA in Chemistry, minor in Mathematics

Isiajah Johnson

Isiajah Johnson

Intern

Woodland Hills, CA

Geoff Pronovost

Geoff Pronovost

Intern

University of California, Riverside

Joan Reger

Joan Reger

Intern

Emory University