Current Research
The Eisenberg Lab applies structural, biochemical, and computational methods to understand the molecular basis of neurodegeneration. Particular projects include the development of small-molecule and peptide-based drugs for Parkinson’s and Alzheimer’s diseases, and the involvement of RNAs in dementias.
In 2022, the Lab used cryo-EM to discover a pharmacophore in the Alzheimer’s-disease-associated fibrils of protein tau. In silico screening into this pharmacophore led to the discovery of small molecules that disassemble the neurotoxic, Alzheimer’s associated fibrils of tau [Reference: “Structure-based discovery of small molecules that disaggregate Alzheimer’s disease tissue derived tau fibrils in vitro,” Paul M. Seidler, Kevin A. Murray, David R. Boyer, Peng Ge, Michael R. Sawaya, Carolyn J. Hu, Xinyi Cheng, Romany Abskharon, Hope Pan, Michael A. De Ture, Christopher K. Williams, Dennis W. Dickson, Harry V. Vinters, David S. Eisenberg, Nature Communications, 13(1):5451 (2022). DOI 10.1038/s41467-022-32951-4. PMID: 36114178. PMCID: PMC9481533.]
In 2023, the Lab found a related small molecule that disassembled the Parkinson’s-disease-associated fibrils of protein alpha-synuclein, and found it active in C.elegans and mouse models of disease. [Reference: . “Small molecules disaggregate alpha-synuclein and prevent seeding from patient brain-derived fibrils,” Kevin A. Murray, Carolyn J Hu, Hope Pan, Jiahui Lu, Romany Abskharon, Jeannette R. Bowler, Gregory M Rosenberg, Christopher K Williams, Gazmend Elezi, Melinda Balbirnie, Kym F Faull Harry V Vinters, Paul M. Seidler, David S. Eisenberg, Proc Natl Acad Sci USA, Feb (2023), doi: 10.1073/pnas.2217835120, PMCID: PMC9963379.]
In 2024, the Lab reported short peptides that also disassemble Alzheimer’s-disease-associated fibrils of tau. [Reference: D-peptide-magnetic nanoparticles fragment tau fibrils and rescue behavioral deficits in a mouse model of Alzheimer’s disease”, Ke Hou, Hope Pan, Hedieh Shahpasand-Kroner, Carolyn Hu, Romany Abskharon, Paul Seidler, Marisa Mekkittikul, Melinda Balbirnie, Carter Lantz, Michael R. Sawaya, Joshua L. Dolinsky, Mychica Jones, Xiaohong Zuo, Joseph A. Loo, Sally Frautschy, Greg Cole and David S. Eisenberg, Science Advances, 10, 2991 (2024)]
Also in 2024, the Lab presented evidence for the mechanism of fibril disassembly by short peptides. [Reference: “How short peptides can disassemble ultra-stable tau fibrils extracted from Alzheimer’s disease brain by a strain-relief mechanism”, Ke Hou, Peng Ge, Michael R. Sawaya, Joshua L. Dolinsky, Yuan Yang, Yi Xiao Jiang, Liisa Lutter, David R. Boyer, Xinyi Cheng, Justin Pi, Jeffrey Zhang, Jiahui Lu, Shixin Yang, Zhiheng Yu, Juli Feigon, David S. Eisenberg, bioRxiv preprint doi: https://doi.org/10.1101/2024.03.25.586668,*
2020-2021 Lab Picture
2015 Lab Picture
