Professor David S. Eisenberg
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
Post Doctoral Fellows
David Boyer
Amyloid fibrils are formed in numerous human diseases, including Alzheimer‘s and Parkinson’s. There is much evidence suggesting that the formation of amyloid fibrils is part of the pathology of these diseases and therefore increasing our understanding of amyloid formation processes is essential for disease diagnosis and intervention. Recent advances in cryo-electron microscopy have enabled the study of the atomic structures of amyloid fibrils extracted from postmortem disease tissue, although these structures only represent the end-stage of the disease. In order to better understand early-stage amyloid diseases, atomic structures of amyloid proteins formed earlier in the disease are needed. These early amyloid structures are termed oligomers since they typically contain only 10-100 copies of the amyloid protein instead of the thousands of copies found in amyloid fibrils. The goal of my project is to determine the atomic structures
of amyloid oligomers using cryo-electron microscopy in order to advance our understanding of amyloid formation processes and possibly enable early-intervention therapeutics for amyloid disease.
Ke Hou
Research interest: Neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s (PD) are characterized by pathological accumulation of amyloid fibrils, like tau in AD and α-synuclein in PD. I am interested in designing peptide disaggregators for these pathological amyloid fibrils based on our newly uncovered “strain-relief mechanism”. Furthermore, I aim to integrate these rationally designed peptides with functional nanomaterials to develop multifunctional platforms for both the diagnosis and therapy of AD and PD.
Sean Jiang
Amyloid diseases are associated with pathological deposits of protein fibrils. Previous work in the field has shown that the structure of fibrils extracted from patient tissues often differ from the fibril structures assembled _in vitro_, underscoring the importance of studying patient-derived samples. I am currently using cryo-EM to study amyloid fibrils purified from autopsied brain tissues of frontotemporal lobar degeneration (FTLD) patients. I am also interested in ocular diseases, including corneal dystrophy and glaucoma. Examining pathological tissues reveals fundamental insights and can lead to surprising discoveries.
Jiahui Lu
My research focuses on the biochemical and structural studies of the low-complexity domain (LCD) of amyloid-like fibrils hnRNPA2 and its conversion to pathogenic amyloid. Disrupting the homeostasis of hnRNPA2 can lead to neurodegenerative diseases such as ALS, FTD, and MSP. I am combining X-ray crystallography, X-ray diffraction, and cryo-electron microscopy to study the atomic-level structures of both the wild-type and the mutant hnRNPA2-LCD fibrils, hoping to discover the mechanism of how a single-point mutation changes functional to pathogenic fibrils. ThT and turbidity assay, and fluorescence microscopy are used to study the liquid-liquid phase separation of hnRNPA2-LCD. Another project of mine is the structural determination of brain-derived ɑ-synuclein (implicated in PD) bound with small molecules, hoping to find possible drug targets.
Einav Tayeb-Fligelman
My research at the Eisenberg lab is dealing with both functional and pathological amyloid. Amyloid are protein fibrils mainly known for their involvement in neurodegeneration. I am studying the interactions and cross-seeding propensity of Tau and Ab, the two key protein players in Alzheimer’s disease. My ultimate goal is to characterize those interactions and to determine the structure of the cross-seeded fibrils. By integrating methods from biochemistry, cell biology, X-ray crystallography, electron microscopy and more, I aim to elucidate and block the Tau-Ab interacting interface. Apart from their pathological roles, some amyloids are functioning in the physiology of the organism producing them. Our lab discovered that the low-complexity domain of the Nucleoprotein of SARS-CoV-2, the virus responsible for Covid-19, is forming amyloid fibrils. In collaboration with additional lab members, and the UCLA Guo and Arumugaswami laboratories, as well as the MSSR facility at CNSI, we are studying the role of the Nucleoprotein- amyloid-formation in the replication of the virus, the possible involvement of those amyloids in the neurodegenerative-related symptoms in Covid-19 patients, and the potential of our designed fibrillation-inhibitors as therapeutics for Covid-19.
Project Scientists
Graduate Students
Josh Dolinsky
Tau is a microtubule-binding protein most highly expressed in neurons, where it stabilizes axonal microtubules. Tau is known to aggregate into putatively toxic amyloid fibrils in a class of neurodegenerative diseases called tauopathies, most notoriously in Alzheimer‘s disease. Polyanions like RNA can act as cofactors for tau fibrillization in vitro, and RNA is known to associate with tau fibrils in Alzheimer’s and other dementias. Fibrillar tau is suspected to disrupt translation in Alzheimer‘s and possibly other diseases, and RNA induces tau to phase separate reversibly. I study the interactions of tau and RNA from a biochemical and structural perspective, especially as is relevant to Alzheimer’s disease.
Undergraduate Students
Vincent Musser
Parkinson’s Disease and Alzheimer’s Disease are the world’s two most common neurodegenerative diseases. Interestingly, both these diseases are associated with the buildup of characteristic amyloid aggregates. Discovering the specific amyloid protein-protein interactions that cause the amyloid aggregation in these diseases could save millions of lives.
In 2022, I joined Dr. Eisenberg’s lab with the goal of better understanding the biochemistry behind these two diseases. Under the supervision of Dr. Melinda Balbirnie, I am investigating small molecules and biomolecules (namely peptides and nanobodies) for use in halting aggregate formation. By utilizing in-vitro and in-vivo assays, testing recombinant and brain-derived samples, and investigating tau and α-synuclein (α-syn), I seek a more complete understanding of the aggregation behaviors seen in these devastating neurodegenerative diseases.
Conrad Wang
Andrew Yoon
Patricia Yu
Research Staff
Duilio Cascio
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.
Michael Sawaya
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.
