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
View All People

contact info:

mailing address:

  • Washington University
  • CB 1134
  • One Brookings Dr.
  • St. Louis, MO 63130
image of book cover

Meredith Jackrel studies protein-misfolding disorders. She also uses protein engineering and directed evolution to develop specialized molecular machines to reverse the protein misfolding implicated in these disorders.

Proteins must fold properly in order to function. 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

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.

Yokom AL, Gates S, Jackrel ME, Mack KL, Su M, Shorter J, and Southworth DR. (2016) Spiral architecture of the Hsp104 disaggregase reveals the structural basis for polypeptide threading. Nat. Struct. Mol. Biol. 23(9):830-7.

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. 

 

Awards

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)