James Shorter

Summary

Affiliation: University of Pennsylvania
Country: USA

Publications

  1. pmc Emergence and natural selection of drug-resistant prions
    James Shorter
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 805b Stellar Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, USA
    Mol Biosyst 6:1115-30. 2010
  2. ncbi request reprint Hsp104: a weapon to combat diverse neurodegenerative disorders
    James Shorter
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6059, USA
    Neurosignals 16:63-74. 2008
  3. pmc The mammalian disaggregase machinery: Hsp110 synergizes with Hsp70 and Hsp40 to catalyze protein disaggregation and reactivation in a cell-free system
    James Shorter
    Stellar Chance Laboratories, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
    PLoS ONE 6:e26319. 2011
  4. pmc Hsp104, Hsp70 and Hsp40 interplay regulates formation, growth and elimination of Sup35 prions
    James Shorter
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Stellar Chance Laboratories, Philadelphia, PA 19104, USA
    EMBO J 27:2712-24. 2008
  5. pmc Operational plasticity enables hsp104 to disaggregate diverse amyloid and nonamyloid clients
    Morgan E Desantis
    Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
    Cell 151:778-93. 2012
  6. pmc A synergistic small-molecule combination directly eradicates diverse prion strain structures
    Blake E Roberts
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, USA
    Nat Chem Biol 5:936-46. 2009
  7. pmc Hsp104 drives "protein-only" positive selection of Sup35 prion strains encoding strong [PSI(+)]
    Morgan E Desantis
    Department of Biochemistry and Biophysics, 805b Stellar Chance Laboratories, Perelman School of Medicine, University of Pennsylvania, 422 Curie Boulevard, Philadelphia, PA 19104, USA
    Chem Biol 19:1400-10. 2012
  8. pmc Applying Hsp104 to protein-misfolding disorders
    Shilpa Vashist
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 805b Stellar Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, USA
    Biochem Cell Biol 88:1-13. 2010
  9. pmc Direct and selective elimination of specific prions and amyloids by 4,5-dianilinophthalimide and analogs
    Huan Wang
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 805b Stellar Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 105:7159-64. 2008
  10. pmc Prion-like disorders: blurring the divide between transmissibility and infectivity
    Mimi Cushman
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 805b Stellar Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, USA
    J Cell Sci 123:1191-201. 2010

Collaborators

Detail Information

Publications32

  1. pmc Emergence and natural selection of drug-resistant prions
    James Shorter
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 805b Stellar Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, USA
    Mol Biosyst 6:1115-30. 2010
    ..Collectively, these advances illuminate the plasticity of prionogenesis and suggest that synergistic combinatorial therapies might circumvent this pathological vicissitude...
  2. ncbi request reprint Hsp104: a weapon to combat diverse neurodegenerative disorders
    James Shorter
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6059, USA
    Neurosignals 16:63-74. 2008
    ..Here, I review the modus operandi of Hsp104 and showcase efforts to unleash Hsp104 on the protein-misfolding events connected to disparate neurodegenerative amyloidoses...
  3. pmc The mammalian disaggregase machinery: Hsp110 synergizes with Hsp70 and Hsp40 to catalyze protein disaggregation and reactivation in a cell-free system
    James Shorter
    Stellar Chance Laboratories, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
    PLoS ONE 6:e26319. 2011
    ..Taken together, these findings suggest that Hsp110 fulfils a subset of Hsp104 activities in mammals. Moreover, they suggest that Hsp104 can collaborate with the mammalian disaggregase machinery to rapidly remodel amyloid conformers...
  4. pmc Hsp104, Hsp70 and Hsp40 interplay regulates formation, growth and elimination of Sup35 prions
    James Shorter
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Stellar Chance Laboratories, Philadelphia, PA 19104, USA
    EMBO J 27:2712-24. 2008
    ..This activity is reduced when Ssa1, or enhanced when Ssb1, is incorporated into nascent prions. These findings illuminate several facets of the chaperone interplay that underpins [PSI(+)] inheritance...
  5. pmc Operational plasticity enables hsp104 to disaggregate diverse amyloid and nonamyloid clients
    Morgan E Desantis
    Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
    Cell 151:778-93. 2012
    ..Thus, operational plasticity enables Hsp104 to robustly dissolve amyloid and nonamyloid clients, which impose distinct mechanical demands...
  6. pmc A synergistic small-molecule combination directly eradicates diverse prion strain structures
    Blake E Roberts
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, USA
    Nat Chem Biol 5:936-46. 2009
    ..Thus, synergistic small-molecule combinations that directly eradicate complete strain repertoires likely hold considerable therapeutic potential...
  7. pmc Hsp104 drives "protein-only" positive selection of Sup35 prion strains encoding strong [PSI(+)]
    Morgan E Desantis
    Department of Biochemistry and Biophysics, 805b Stellar Chance Laboratories, Perelman School of Medicine, University of Pennsylvania, 422 Curie Boulevard, Philadelphia, PA 19104, USA
    Chem Biol 19:1400-10. 2012
    ..Thus, we illuminate direct mechanisms underpinning how the proteostasis network can drive prion strain selection...
  8. pmc Applying Hsp104 to protein-misfolding disorders
    Shilpa Vashist
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 805b Stellar Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, USA
    Biochem Cell Biol 88:1-13. 2010
    ..Importantly, Hsp104 antagonizes the degeneration of dopaminergic neurons induced by alpha-synuclein misfolding in the rat substantia nigra. These studies raise hopes for developing Hsp104 as a therapeutic agent...
  9. pmc Direct and selective elimination of specific prions and amyloids by 4,5-dianilinophthalimide and analogs
    Huan Wang
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 805b Stellar Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 105:7159-64. 2008
    ..Our studies provide mechanistic insights and reinvigorate hopes for small-molecule therapies that specifically disrupt intermolecular amyloid contacts...
  10. pmc Prion-like disorders: blurring the divide between transmissibility and infectivity
    Mimi Cushman
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 805b Stellar Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, USA
    J Cell Sci 123:1191-201. 2010
    ..In this Commentary, we suggest how these treatments might be optimized to overcome the transmissible conformers that confer neurodegeneration...
  11. pmc Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS
    Zhihui Sun
    Department of Cell and Developmental Biology, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
    PLoS Biol 9:e1000614. 2011
    ..Our findings suggest that TDP-43 and FUS, though similar RNA-binding proteins, aggregate and confer disease phenotypes via distinct mechanisms. These differences will likely have important therapeutic implications...
  12. pmc Stress granules as crucibles of ALS pathogenesis
    Yun R Li
    Medical Scientist Training Program and, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
    J Cell Biol 201:361-72. 2013
    ..Recent work connecting TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves protein aggregation as part of its normal function, might be coopted during disease pathogenesis...
  13. pmc A yeast functional screen predicts new candidate ALS disease genes
    Julien Couthouis
    Departments of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 108:20881-90. 2011
    ....
  14. pmc N-terminal domains elicit formation of functional Pmel17 amyloid fibrils
    BRENDA WATT
    Departments of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 284:35543-55. 2009
    ..These data define the structural core of Pmel17 amyloid, imply that the RPT domain plays a regulatory role in timing amyloid conversion, and suggest that fibril formation might be physically linked with multivesicular body sorting...
  15. pmc The Mad2 partial unfolding model: regulating mitosis through Mad2 conformational switching
    John J Skinner
    Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA
    J Cell Biol 183:761-8. 2008
    ..Recent structural, biochemical, and cell biological advances suggest that the catalyzed conversion of Mad2 requires a major structural rearrangement that transits through a partially unfolded intermediate...
  16. pmc Prion proteostasis: Hsp104 meets its supporting cast
    Elizabeth A Sweeny
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    Prion 2:135-40. 2008
    ..Here, we spotlight recent advances that begin to clarify this issue. We suggest that the Hsp70:Hsp40 chaperone machinery functions collectively as a rheostat that adjusts Hsp104's basic prion-remodeling activities...
  17. pmc RNA-binding proteins with prion-like domains in ALS and FTLD-U
    Aaron D Gitler
    Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
    Prion 5:179-87. 2011
    ..Collectively, however, our findings lead us to suggest that FUS and TDP-43, though similar RNA-binding proteins, likely aggregate and confer disease phenotypes via distinct mechanisms...
  18. doi request reprint Potentiated hsp104 variants antagonize diverse proteotoxic misfolding events
    Meredith E Jackrel
    Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
    Cell 156:170-82. 2014
    ..Our work establishes that disease-associated aggregates and amyloid are tractable targets and that enhanced disaggregases can restore proteostasis and mitigate neurodegeneration. ..
  19. pmc Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models
    Maria Armakola
    Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
    Nat Genet 44:1302-9. 2012
    ..Our findings provide insight into TDP-43-mediated cytotoxicity and suggest that decreasing Dbr1 activity could be a potential therapeutic approach for ALS...
  20. pmc The elusive middle domain of Hsp104 and ClpB: location and function
    Morgan E Desantis
    Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, 805b Stellar Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, USA
    Biochim Biophys Acta 1823:29-39. 2012
    ....
  21. pmc TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity
    Brian S Johnson
    Department of Cell and Developmental Biology, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 284:20329-39. 2009
    ..Thus, TDP-43 is intrinsically aggregation-prone, and its propensity for toxic misfolding trajectories is accentuated by specific ALS-linked mutations...
  22. pmc Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model
    Mimi Cushman-Nick
    Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
    PLoS Genet 9:e1003781. 2013
    ..Thus, we establish the first disaggregase or chaperone treatment administered after the onset of pathogenic protein-induced degeneration that mitigates disease progression. ..
  23. ncbi request reprint Prions as adaptive conduits of memory and inheritance
    James Shorter
    Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA
    Nat Rev Genet 6:435-50. 2005
    ..We then describe situations in which prion-enciphered events might have essential roles in long-term memory formation, transcriptional memory and genome-wide expression patterns...
  24. pmc Destruction or potentiation of different prions catalyzed by similar Hsp104 remodeling activities
    James Shorter
    Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA
    Mol Cell 23:425-38. 2006
    ..In vivid distinction, the endpoint of Ure2 fragmentation is short prion fibers with enhanced infectivity and self-replicating ability. These advances explain the distinct effects of Hsp104 on the inheritance of the two prions...
  25. pmc Asymmetric deceleration of ClpB or Hsp104 ATPase activity unleashes protein-remodeling activity
    Shannon M Doyle
    Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health NIH, Bethesda, Maryland 20892, USA
    Nat Struct Mol Biol 14:114-22. 2007
    ..We suggest that this versatility in reaction mechanism enables ClpB and Hsp104 to reactivate the entire aggregated proteome after stress and enables Hsp104 to control prion inheritance...
  26. pmc Atypical AAA+ subunit packing creates an expanded cavity for disaggregation by the protein-remodeling factor Hsp104
    Petra Wendler
    Department of Crystallography, Birkbeck College, Malet Street, London WC1E 7HX, UK
    Cell 131:1366-77. 2007
    ..The large cavity could enable the uptake of polypeptide loops without a requirement for exposed N or C termini...
  27. pmc Hsp104 antagonizes alpha-synuclein aggregation and reduces dopaminergic degeneration in a rat model of Parkinson disease
    Christophe Lo Bianco
    Wallenberg Neuroscience Center, Division of Neurobiology, Department of Experimental Medical Science, Lund University, Lund, Sweden
    J Clin Invest 118:3087-97. 2008
    ..Hsp104 likely protects dopaminergic neurons by antagonizing toxic alpha-synuclein assemblies and might have therapeutic potential for PD and other neurodegenerative amyloidoses...
  28. ncbi request reprint Hsp104 catalyzes formation and elimination of self-replicating Sup35 prion conformers
    James Shorter
    Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA
    Science 304:1793-7. 2004
    ..These Hsp104 activities differed in their reaction mechanism and can explain [PSI+] inheritance patterns...
  29. pmc The Parkinson's disease protein alpha-synuclein disrupts cellular Rab homeostasis
    Aaron D Gitler
    Whitehead Institute for Biomedical Research and Howard Hughes Medical Institute, Cambridge, MA 02142, USA
    Proc Natl Acad Sci U S A 105:145-50. 2008
    ..Thus, alpha-syn causes general defects in vesicle trafficking, to which dopaminergic neurons are especially sensitive...
  30. pmc Hsp110 chaperones regulate prion formation and propagation in S. cerevisiae by two discrete activities
    Heather Sadlish
    Zentrum für Molekulare Biologie der Universität Heidelberg ZMBH, DKFZ ZMBH Alliance, Universitat Heidelberg, Heidelberg, Germany
    PLoS ONE 3:e1763. 2008
    ..This activity is not essential for prion formation under conditions of Sup35 overproduction, however, it may be relevant for spontaneous [PSI(+)] formation as well as for protection of the prion trait upon physiological Hsp104 induction...
  31. ncbi request reprint A cryptic Rab1-binding site in the p115 tethering protein
    Matthew Beard
    Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA
    J Biol Chem 280:25840-8. 2005
    ..Regulation of this interaction by proteins such as GM130 and Giantin may control the membrane recruitment of p115 by Rab1...
  32. ncbi request reprint Navigating the ClpB channel to solution
    James Shorter
    Nat Struct Mol Biol 12:4-6. 2005