Dailu Chen, Ph.D.

Molecular Biophysics | Mentor: Łukasz Joachimiak, Ph.D.

From: Nanjing, China
Undergraduate: Physiology, minor in math, University of Arizona
Thesis work: Early conformational changes that drive tau aggregation

First, she found that normally, the intrinsically disordered tau resists aggregation, and that in disease the monomer misfolds into stable conformations that seed aggregation. She used structural studies and modeling to uncover conformational changes and found that local interactions with an amyloid motif regulate conversion to the pathogenic form.

She also developed peptide systems to mimic this process and found that conformational changes around a stabilizing beta-turn determine tau’s propensity to aggregate. In subsequent work, she confirmed that post-translational modifications in tau don’t affect folding into pathogenic conformations.

Finally, she used a multi-disciplinary approach to understand how a familial mutation in tau, s320F, drives spontaneous aggregation. Her work uncovered nuanced mechanisms of regulation that suggest how to limit aggregation.

After graduation: Dailu became a consultant in California.

Publications

Cross-Linking Mass Spectrometry Analysis of Metastable Compact Structures in Intrinsically Disordered Proteins Chen D, Joachimiak LA. Methods Mol Biol. 2023;2551:189-201. doi: 10.1007/978-1-0716-2597-2_13.

Seed-competent tau monomer initiates pathology in a tauopathy mouse model
Mirbaha H, Chen D, Mullapudi V, Terpack SJ, White CL, Joachimiak LA, Diamond MI
J Biol Chem. 2022 Aug;298(8):102163. doi: 10.1016/j.jbc.2022.102163.

FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation. Chen D, Wosztyl A, Mullapudi V, Bali S, Vaquer-Alicea J, Melhem S, Seelaar H, van Swieten JC, Diamond MI, Joachimiak LA. bioRxiv 2022.08.11.503511; doi: https://doi.org/10.1101/2022.08.11.503511.

Tau local structure shields an amyloid-forming motif and controls aggregation propensity. Chen D, Drombosky KW, Hou Z, Sari L, Kashmer OM, Ryder BD, Perez VA, Woodard DR, Lin MM, Diamond MI, Joachimiak LA. Nat Commun. 2019 Jun 7;10(1):2493. doi: 10.1038/s41467-019-10355-1.

Inert and seed-competent tau monomers suggest structural origins of aggregation. Mirbaha H, Chen D, Morazova OA, Ruff KM, Sharma AM, Liu X, Goodarzi M, Pappu RV, Colby DW, Mirzaei H, Joachimiak LA, Diamond MI. Elife. 2018 Jul 10;7:e36584. doi: 10.7554/eLife.36584.

Michael LaCroix, Ph.D.

Biophysics | Mentor: Marc Diamond, Ph.D.

From: Buffalo, Minnesota
Undergraduate: Neuroscience, a minor in psychology, U of M Twin Cities
Thesis work: Whether tau seeding is a normal process that occurs in healthy brains.

Michael developed a monoclonal antibody (MD3.1) that binds to tau seeds from healthy brains but not seeds from neurodegenerative diseases. The antibody showed that healthy brains have tau seeds in the parietal cortex, and these tau levels didn’t change with age, as expected.

After graduation: Michael went to medical school via UT Southwestern's Medical Scientist Training Program.

Publications

Tau seeding without tauopathy. LaCroix MS, Hitt BD, Beaver JD, Estill-Terpack S, Gleason K, Tamminga CA, Evers BM, White CL, Diamond MI. bioRxiv (2022) doi: https://doi.org/10.1101/2022.02.03.479049

Tau seeds translocate across the cell membrane to initiate aggregation. Dodd DA, LaCroix M, Valdez C, Knox GM, Vega AR, Kumar A, Xing C, White CL, View Diamond MI. bioRxiv (2022) doi: https://doi.org/10.1101/2022.05.10.491429

Bryan Ryder, Ph.D.

Molecular Biophysics | Mentor: Łukasz Joachimiak, Ph.D.

From: Hillsborough, New Jersey
Undergraduate: Biochemistry. Rutgers University
Thesis work: Biophysics of the “chaperone” protein DNAJB8, which disrupts aggregation of tau protein.

Bryan found that two regions of DNAJB8 help control when DNAJB8 can bind to another chaperone, Hsp70. He also found that a motif of six amino acids helps DNAJB8 self-assemble, and that disrupting this motif allows DNAJB8 to better delay tau aggregation in vitro.

These findings are significant to our overall work because DnaJB8 belongs to the Hsp40 class of chaperone proteins, which suppress protein aggregation.

After graduation: Bryan went to a postdoctoral fellowship with Jason Gestwicki at UCSF's Institute for Neurodegenerative Diseases.

Publications

Chaperoning shape-shifting tau in disease. Ryder BD, Wydorski PM, Hou Z, Joachimiak ŁA.Trends Biochem Sci. 2022 Apr;47(4):301-313. doi: 10.1016/j.tibs.2021.12.009.

Regulatory inter-domain interactions influence Hsp70 recruitment to the DnaJB8 chaperone. Ryder, BD, Matlahov, I, Bali, S, Vaquer-Alicea, J, van der Wel, PCA, Joachimiak, Ł. Nat Commun 2021 12, 946. doi:10.1038/s41467-021-21147-x

Biophysical properties of a tau seed. Hou, Z, Chen, D, Ryder, BD, Joachimiak, Ł. Sci Rep 11, 13602 (2021). doi: 10.1038/s41598-021-93093-z

DnaJC7 binds natively folded structural elements in tau to inhibit amyloid formation. Hou Z, Wydorski PM, Perez VA, Mendoza-Oliva A, Ryder BD, Mirbaha H, Kashmer O, Joachimiak LA. Nat Commun. 2021 Sep 9;12(1):5338. doi: 10.1038/s41467-021-25635-y.

Tau local structure shields an amyloid-forming motif and controls aggregation propensity. Chen D, Drombosky KW, Hou Z, Sari L, Kashmer OM, Ryder BD, Perez VA, Woodard DR, Lin MM, Diamond MI, Joachimiak ŁA. Nat Commun. 2019 Jun 7;10(1):2493. doi: 10.1038/s41467-019-10355-1.

Amy Zwierzchowski-Zarate, Ph.D.

Neuroscience | Mentor: Marc Diamond, Ph.D.

From: Chicago
Undergraduate: Combined B.S./M.S. in neuroscience, UT Dallas
Thesis work: RNA interactions with tau protein as it becomes a “seed” that recruits other tau proteins to adopt the same shape and to clump together

Amy found that specific sequences of RNA induce conformational changes in tau that lead to seeding and assembly. She also found that RNA sequences influence tau to form different shapes, or strains, associated with various diseases. Finally, Amy found that RNA stabilizes tau seeds, and that if RNA is removed, the tau protein no longer acts as a seed.

She plans to pursue teaching and science communication roles, as well as opportunities to build and grow STEM outreach programs.

Publications

RNA induces unique tau strains and stabilizes Alzheimer's disease seeds Zwierzchowski-Zarate AN, Mendoza-Oliva A, Kashmer OM, Collazo-Lopez JE, White CL, Diamond MI. J Biol Chem. 2022 Jun 11:102132. doi: 10.1016/j.jbc.2022.102132. Online ahead of print.