Meredith Jackrel

Meredith Jackrel

Assistant Professor of Chemistry
Postdoctoral Fellow, University of Pennsylvania
PhD, Yale University
BS, The College of New Jersey
research interests:
  • Protein folding, misfolding, and neurodegenerative disease
  • Protein chaperones
  • Protein engineering
  • Amyloid
  • Motor proteins

contact info:

mailing address:

  • Washington University
    CB 1134
    One Brookings Dr.
    St. Louis, MO 63130

Meredith Jackrel studies protein-misfolding disorders. She also uses protein engineering and directed evolution to tune protein disaggregases to reverse the protein misfolding implicated in these disorders.

Protein folding is an essential process, and so when protein misfolding occurs, severe problems can arise. Indeed, protein misfolding underpins many devastating neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. We are interested in understanding how protein misfolding occurs, how it can lead to disease, and how protein-remodeling factors can prevent or even reverse misfolding. We are particularly interested in protein disaggregases. Protein disaggregases are capable of solubilizing proteins from highly stable species such as amyloid and disordered aggregates. We are interested in better understanding how protein disaggregases solubilize such highly stable species. We are also interested in employing protein engineering techniques to tune the properties of disaggregases.

While amyloid is an extraordinarily stable protein conformer typically implicated in disease, yeast have harnessed the amyloid fold for beneficial purposes. The AAA+ protein Hsp104 regulates beneficial amyloid in yeast. We have shown that Hsp104 also has activity against several proteins implicated in human disease. Furthermore, we have used protein engineering to boost the activity of Hsp104, and these variants can suppress dopaminergic neurodegeneration in an animal model of Parkinson’s disease.

These first-generation variants are highly promising, but require further tuning to improve their characteristics. Thus we employ protein engineering and directed evolution to tune the activity of Hsp104 and other chaperones in order to develop protein-remodeling factors with desired properties. We predict that just as numerous proteins have evolved from generalists to specialists over many years of evolution, we can evolve Hsp104 from a generalist to a specialized molecular machine. We are also interested in testing the variants in various model systems including C. elegans, Drosophila, and motor neurons derived from reprogrammed patient fibroblasts. Finally, we also employ pure protein biochemistry and structural biology to better understand the structure and mechanism of protein-remodeling factors. Amyloid is incredibly stable, thus we seek to understand how these molecular machines disassemble amyloid.

Selected Publications

Sprunger ML, Lee K, Sohn BS, and Jackrel ME. (2022). Molecular determinants and modifiers of Matrin-3 toxicity, condensate dynamics, and droplet morphology. iScience. 25(3):103900.


Ryan JJ, Bao A, Bell B, Ling C, and Jackrel ME. (2021). Drivers of Hsp104 potentiation revealed by scanning mutagenesis of the middle domain. Protein Science. 30(8):1667-1685.


Howard MK, Sohn BS, von Borcke J, Xu A, and Jackrel ME. (2020). Functional analysis of proposed substrate-binding residues of Hsp104. PLoS ONE. 15(3):e0230198.

Ryan JJ, Sprunger ML, Holthaus K, Shorter J, and Jackrel ME. (2019). Engineered protein disaggregases mitigate toxicity of aberrant prion-like fusion proteins underlying sarcoma. J. Biol. Chem. 294(29):11286-11296.


Guo L, Kim HJ, Wang H, Monaghan J, Freyermuth F, Sung JC, O'Donovan K, Fare CM, Diaz Z, Singh N, Zhang ZC, Coughlin M, Sweeny EA, DeSantis ME, Jackrel ME, Rodell CB, Burdick JA, King OD, Gitler AD, Lagier-Tourenne C, Pandey UB, Chook YM, Taylor JP, Shorter J. (2018) Nuclear-import receptors reverse aberrant phase transitions of RNA-binding proteins with prion-like domains. Cell. 173(3):677-692.

Gates SN, Yokom AL, Lin J, Jackrel ME, Rizo AN, Kendsersky NM, Buell CE, Sweeny EA, Mack KL, Chuang E, Torrente MP, Su M, Shorter J, Southworth DR. (2017) Ratchet-like polypeptide translocation mechanism of the AAA+ disaggregase Hsp104. Science. 357(6348):273-279.

Jackrel ME, Yee K, Tariq A, Chen AI, and Shorter J. (2015) Disparate mutations confer therapeutic gain of Hsp104 function. ACS Chemical Biology. 10(12):2672-2679.

Sweeny EA, Jackrel ME, Go MS, Sochor MA, Razzo BM, DeSantis ME, Gupta K, and Shorter J. (2015) The Hsp104 N-terminal domain enables disaggregase plasticity and potentiation. Mol. Cell. 57(5): 836-849.

Jackrel ME and Shorter J. (2014) Potentiated Hsp104 variants suppress toxicity of diverse neurodegenerative disease-linked proteins. Dis. Model Mech. 7(10):1175-1184.

Jackrel ME, DeSantis ME, Martinez BA, Castellano LM, Stewart RM, Caldwell KA, Caldwell GA, and Shorter J. (2014) Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events. Cell. 156:170-182.

DeSantis ME, Leung EH, Sweeny EA, Jackrel ME, Cushman M, Neuhaus-Follini AN, Vashist S, Sochor MA, Knight MN, and Shorter J. (2012) Operational plasticity enables Hsp104 to disaggregate diverse amyloid and non-amyloid clients. Cell. 151:778-793.


American Heart Association Career Development Award (2020)
Maximizing Investigators’ Research Award (MIRA), NIH/NIGMS (2018)
Laureate, Frick Foundation for ALS Research (2017)
Target ALS Springboard Fellow (2014-2017)
Finalist, Regeneron Prize for Creative Innovation by a Postdoctoral Fellow (2014)
American Heart Association Postdoctoral Fellow (2011-2014)