Assistant Professor of Biochemistry and Biophysics

Location: 805B Stellar-Chance Laboratories
Office: (215) 573-4256
Lab: (215) 573-4257
Email: jshorter@mail.med.upenn.edu

B.A. 1995 Keble College, Oxford University (Biology)
Ph.D. 2000 Imperial Cancer Research Fund, University College London (Cell Biology)

Shorter Lab

October, 2007: Dr. Shorter wins a 2007 NIH Director's New Innovator Award

DESCRIPTION OF RESEARCH INTERESTS: 

Life demands that proteins fold into elaborate structures to perform the overwhelming majority of biological functions. We investigate how cells achieve such successful protein folding. In particular, we seek to understand how cells prevent, reverse, or even promote the formation of prion and amyloid fibers.

Amyloid fibers are self-perpetuating protein aggregates. They self-replicate their specific 'cross-β' conformation at their growing ends, by converting other copies of the same protein to the 'cross-β' amyloid form. When amyloid fibers grow and divide with high efficiency they can be infectious, and are then termed prions. Cells have evolved a sophisticated machinery to alleviate such aberrant protein aggregation. For example, protein-remodeling factors resolve protein aggregates, molecular chaperones prevent protein aggregation, osmolytes act as chemical chaperones, and degradation systems eliminate misfolded proteins. Nonetheless, these safeguards can be breached, especially as organisms age, and the consequences are often fatal. Prion and amyloid formation are associated with some of the most devastating neurodegenerative diseases confronting humankind, including Alzheimer's disease, Parkinson's disease, and variant Creutzfeldt-Jacob disease. Yet, surprisingly, it is becoming increasingly clear that prions and amyloids are not always a problem. In fact, several have been harnessed during evolution for adaptive purposes and feature in some of the most revolutionary new concepts in biology and evolution, including protein-based genetic elements, long-term memory formation, melanosome biogenesis, evolutionary capacitance and the revelation of cryptic genetic variation. We employ biochemistry and genetics to understand the enigmatic mechanistic interfaces that exist between protein-remodeling factors, molecular chaperones, small molecules and amyloid/prion fibers, and how these interfaces can be manipulated to divert pathogenic and promote beneficial phenotypic trajectories. Specifically, we are taking three broad approaches:

1. Defining the mechanisms of Hsp104 function.

Dr. Shorter's focus concerns Hsp104, a protein-remodeling factor of the AAA+ superfamily from yeast, which disaggregates denatured proteins and returns them to normal function. Hsp104 is also essential for the formation and inheritance of several yeast prions; protein-based genetic elements comprised of amyloid fibers that self-perpetuate alterations in protein form and function. Hsp104 can both construct and deconstruct self-replicating amyloid conformers of Sup35, which comprise the yeast prion [PSI⁺], and Ure2, which comprise the yeast prion [URE3]. We strive to understand the mechanistic basis of how Hsp104 structure enables these disaggregation activities and other prion-regulatory functions.

Hsp104 is often assisted by a supporting cast of molecular chaperones to rescue aggregated polypeptides. Most notably, Hsp70, Hsp40 and small heat shock proteins synergize with Hsp104 to promote the reactivation of protein aggregates. We wish to understand how these molecular chaperones achieve these synergistic activities.

2. Applying Hsp104 to disease-associated amyloidogenesis.

Inexplicably, Hsp104 has no known homologue in metazoa. Indeed, whether mammals possess an analogous protein disaggregase (AAA+ protein or otherwise) remains an important open question. This is vexing, for it would seem that a protein that reverses protein aggregation and restores protein function, would be critical in our fight against several diseases caused by aberrant protein aggregation. Hence, we engineer and apply Hsp104 to metazoan systems to antagonize and reverse the proteotoxic aggregation pathways that are intimately connected with Parkinson's, Alzheimer's and Huntington's disease. We are also keen to identify whether there is a metazoan AAA+ protein that can perform a similar function to Hsp104.

3. Defining how small molecules disrupt amyloid structure.

Finally, we study a small molecule, 4,5-dianilinophthalimide, which dissolves Aβ42 fibers (that occur in Alzheimer’s disease) and eliminates their neurotoxicity, and also disrupts prion structure and function. We are interested in defining the mechanisms by which this small molecule disrupts amyloid structure. Further, we seek to elucidate synergies between small molecules and protein-remodeling factors that may accelerate the disruption of specific amyloid oligomers and fibers.

RECENT PUBLICATIONS

1. Shorter, J. (2008) Hsp104: a weapon to combat diverse neurodegenerative disorders. Neurosignals 16:63-74. pdf file
2. Gitler, A.D., Bevis, B.J., Shorter, J., Strathearn, K.E., Hamamichi, S., Su, L.J., Caldwell, K.A., Caldwell, G.A., Rochet, J.C., McCaffery, J.M., et al. (2008) The Parkinson's disease protein {alpha}-synuclein disrupts cellular Rab homeostasis. Proc Natl Acad Sci USA 105(1):145-150. pdf file
3. Wendler, P., Shorter, J., Plisson, C., Cashikar, A.G., Lindquist, S., and Saibil, H.R. (2007) Atypical AAA+ subunit packing creates an expanded cavity for disaggregation by the protein-remodeling factor Hsp104. Cell 131:1366-1377. pdf file
4. Gitler, A. D., and Shorter, J. (2007) Prime time for alpha-synuclein. J. Neurosci. 27:2433-2434. pdf file
5. Doyle, S. M., Shorter, J., Zolkiewski, M., Hoskins, J. R., Lindquist, S., and Wickner, S. (2007) Asymmetric deceleration of ClpB or Hsp104 ATPase activity unleashes protein-remodeling activity. Nat. Struct. Mol. Biol. 14:114-122. pdf file
6. Shorter, J., and Lindquist, S. (2006) Destruction or potentiation of different prions catalyzed by similar Hsp104 remodeling activities. Mol. Cell 23:425-438. pdf file
7. Shorter, J., and Lindquist, S. (2005) Prions as adaptive conduits of memory and inheritance. Nat. Rev. Genetics 6:435-450. pdf file
8. Shorter, J., and Lindquist, S. (2005) Navigating the ClpB channel to solution. Nat. Struct. Mol. Biol. 12:4-6. pdf file
9. Shorter, J., and Lindquist, S. (2004) Hsp104 catalyzes formation and elimination of self-replicating Sup35 prion conformers. Science 304:1793-1797. pdf file
10. Meyer, H. H., Shorter, J. G., Seemann, J., Pappin, D., and Warren, G. (2000) A complex of mammalian ufd1 and npl4 links the AAA-ATPase, p97, to ubiquitin and nuclear transport pathways. Embo J. 19:2181-2192. pdf file