Research Topics
Genomes and Genes | James ShorterSummaryAffiliation: University of Pennsylvania Country: USA Publications
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Publications
Emergence and natural selection of drug-resistant prionsJames 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...- Hsp104, Hsp70 and Hsp40 interplay regulates formation, growth and elimination of Sup35 prionsJames 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... - The mammalian disaggregase machinery: Hsp110 synergizes with Hsp70 and Hsp40 to catalyze protein disaggregation and reactivation in a cell-free systemJames 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... 
Hsp104: a weapon to combat diverse neurodegenerative disordersJames 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...- Operational plasticity enables hsp104 to disaggregate diverse amyloid and nonamyloid clientsMorgan 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... - A synergistic small-molecule combination directly eradicates diverse prion strain structuresBlake 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... - Direct and selective elimination of specific prions and amyloids by 4,5-dianilinophthalimide and analogsHuan 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... - Applying Hsp104 to protein-misfolding disordersShilpa 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... - Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLSZhihui 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... - Prion-like disorders: blurring the divide between transmissibility and infectivityMimi 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... - A yeast functional screen predicts new candidate ALS disease genesJulien 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.... - N-terminal domains elicit formation of functional Pmel17 amyloid fibrilsBRENDA 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... - Prion proteostasis: Hsp104 meets its supporting castElizabeth 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... - The Mad2 partial unfolding model: regulating mitosis through Mad2 conformational switchingJohn 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... - RNA-binding proteins with prion-like domains in ALS and FTLD-UAaron 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... - Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease modelsMaria 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... - The elusive middle domain of Hsp104 and ClpB: location and functionMorgan 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.... - TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicityBrian 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... - 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... - Prions as adaptive conduits of memory and inheritanceJames 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... - Destruction or potentiation of different prions catalyzed by similar Hsp104 remodeling activitiesJames 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... - Asymmetric deceleration of ClpB or Hsp104 ATPase activity unleashes protein-remodeling activityShannon 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... - Atypical AAA+ subunit packing creates an expanded cavity for disaggregation by the protein-remodeling factor Hsp104Petra 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... - Hsp104 antagonizes alpha-synuclein aggregation and reduces dopaminergic degeneration in a rat model of Parkinson diseaseChristophe 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... - Hsp104 catalyzes formation and elimination of self-replicating Sup35 prion conformersJames 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... - The Parkinson's disease protein alpha-synuclein disrupts cellular Rab homeostasisAaron 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... - Hsp110 chaperones regulate prion formation and propagation in S. cerevisiae by two discrete activitiesHeather 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... - A cryptic Rab1-binding site in the p115 tethering proteinMatthew 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... - Navigating the ClpB channel to solutionJames Shorter
Nat Struct Mol Biol 12:4-6. 2005