Therapeutic genetic variation revealed in diverse Hsp104 homologs

March, Zachary M.; Sweeney, Katelyn; Kim, Hanna; Yan, Xiaohui; Castellano, Laura M.; Jackrel, Meredith E.; Lin, JiaBei; Chuang, Edward; Gomes, Edward; Willicott, Corey W.; Michalska, Karolina; Jedrzejczak, Robert P.; Joachimiak, Andrzej; Caldwell, Kim A.; Caldwell, Guy A.; Shalem, Ophir; Shorter, James

doi:10.7554/elife.57457

Therapeutic genetic variation revealed in diverse Hsp104 homologs

Journal Article · Tue Dec 15 00:00:00 EST 2020 · eLife

DOI:https://doi.org/10.7554/elife.57457· OSTI ID:1768600

^[1]; Sweeney, Katelyn ^[2]; Kim, Hanna ^[3]; Yan, Xiaohui ^[3]; Castellano, Laura M. ^[1]; ^[4]; Lin, JiaBei ^[1]; Chuang, Edward ^[1]; Gomes, Edward ^[1]; Willicott, Corey W. ^[3]; Michalska, Karolina ^[5]; Jedrzejczak, Robert P. ^[6]; Joachimiak, Andrzej ^[5]; ^[3]; Caldwell, Guy A. ^[3]; Shalem, Ophir ^[2]; ^[1]

Univ. of Pennsylvania, Philadelphia, PA (United States)
Univ. of Pennsylvania, Philadelphia, PA (United States); Children's Hospital of Philadelphia, PA (United States). Center for Cellular and Molecular Therapeutics
Univ. of Alabama, Tuscaloosa, AL (United States)
Univ. of Pennsylvania, Philadelphia, PA (United States); Washington Univ., St. Louis, MO (United States)
Argonne National Lab. (ANL), Argonne, IL (United States). Structural Biology Center; Univ. of Chicago, IL (United States)
Argonne National Lab. (ANL), Argonne, IL (United States). Structural Biology Center

The AAA+ protein disaggregase, Hsp104, increases fitness under stress by reversing stress-induced protein aggregation. Natural Hsp104 variants might exist with enhanced, selective activity against neurodegenerative disease substrates. However, natural Hsp104 variation remains largely unexplored. Here, we screened a cross-kingdom collection of Hsp104 homologs in yeast proteotoxicity models. Prokaryotic ClpG reduced TDP-43, FUS, and α-synuclein toxicity, whereas prokaryotic ClpB and hyperactive variants were ineffective. Furthermore, we uncovered therapeutic genetic variation among eukaryotic Hsp104 homologs that specifically antagonized TDP-43 condensation and toxicity in yeast and TDP-43 aggregation in human cells. We also uncovered distinct eukaryotic Hsp104 homologs that selectively antagonized α-synuclein condensation and toxicity in yeast and dopaminergic neurodegeneration in C. elegans. Surprisingly, this therapeutic variation did not manifest as enhanced disaggregase activity, but rather as increased passive inhibition of aggregation of specific substrates. By exploring natural tuning of this passive Hsp104 activity, we elucidated enhanced, substrate-specific agents that counter proteotoxicity underlying neurodegeneration.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: Blavatnik Family Foundation; John Hopkins University; Life Extension Foundation; Linda Pechenik Montague Investigator Award; Muscular Dystrophy Association; National Institutes of Health (NIH); National Science Foundation (NSF); Target ALS Foundation; USDOE

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1768600

Journal Information:: eLife, Journal Name: eLife Vol. 9; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: English

References (134)

A Stearoyl–Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in α ‐Synuclein Mice Nuber, Silke; Nam, Alice Y.; Rajsombath, Molly M. Annals of Neurology, Vol. 89, Issue 1 https://doi.org/10.1002/ana.25920	journal	October 2020
A suite of Gateway ^® cloning vectors for high-throughput genetic analysis in Saccharomyces cerevisiae Alberti, Simon; Gitler, Aaron D.; Lindquist, Susan Yeast, Vol. 24, Issue 10 https://doi.org/10.1002/yea.1502	journal	October 2007
Vesicle trafficking and lipid metabolism in synucleinopathy Fanning, Saranna; Selkoe, Dennis; Dettmer, Ulf Acta Neuropathologica https://doi.org/10.1007/s00401-020-02177-z	journal	June 2020
Mitochondrial Hsp78, a member of the Clp/Hsp100 family in Saccharomyces cerevisiae , cooperates with Hsp70 in protein refolding Krzewska, Joanna; Langer, Thomas; Liberek, Krzysztof FEBS Letters, Vol. 489, Issue 1 https://doi.org/10.1016/S0014-5793(00)02423-6	journal	January 2001
Saccharomyces cerevisiae Hsp104 protein. Purification and characterization of ATP-induced structural changes. Parsell, D. A.; Kowal, A. S.; Lindquist, S. Journal of Biological Chemistry, Vol. 269, Issue 6 https://doi.org/10.1016/S0021-9258(17)41804-7	journal	February 1994
The elusive middle domain of Hsp104 and ClpB: Location and function DeSantis, Morgan E.; Shorter, James Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. 1823, Issue 1 https://doi.org/10.1016/j.bbamcr.2011.07.014	journal	January 2012
Heat shock protein 104 inhibited the fibrillization of prion peptide 106–126 and disassembled prion peptide 106–126 fibrils in vitro Liu, Ying-Hui; Han, Yan-Ling; Song, Juan The International Journal of Biochemistry & Cell Biology, Vol. 43, Issue 5 https://doi.org/10.1016/j.biocel.2011.01.022	journal	May 2011
AAA+ Protein-Based Technologies to Counter Neurodegenerative Disease March, Zachary M.; Mack, Korrie L.; Shorter, James Biophysical Journal, Vol. 116, Issue 8 https://doi.org/10.1016/j.bpj.2019.03.007	journal	April 2019
Prion-like domains as epigenetic regulators, scaffolds for subcellular organization, and drivers of neurodegenerative disease March, Zachary M.; King, Oliver D.; Shorter, James Brain Research, Vol. 1647 https://doi.org/10.1016/j.brainres.2016.02.037	journal	September 2016
Semen-Derived Amyloid Fibrils Drastically Enhance HIV Infection Münch, Jan; Rücker, Elke; Ständker, Ludger Cell, Vol. 131, Issue 6 https://doi.org/10.1016/j.cell.2007.10.014	journal	December 2007
Operational Plasticity Enables Hsp104 to Disaggregate Diverse Amyloid and Nonamyloid Clients DeSantis, Morgan E.; Leung, Eunice H.; Sweeny, Elizabeth A. Cell, Vol. 151, Issue 4 https://doi.org/10.1016/j.cell.2012.09.038	journal	November 2012
Potentiated Hsp104 Variants Antagonize Diverse Proteotoxic Misfolding Events Jackrel, Meredith E.; DeSantis, Morgan E.; Martinez, Bryan A. Cell, Vol. 156, Issue 1-2 https://doi.org/10.1016/j.cell.2013.11.047	journal	January 2014
Reversible, Specific, Active Aggregates of Endogenous Proteins Assemble upon Heat Stress Wallace, Edward W. J.; Kear-Scott, Jamie L.; Pilipenko, Evgeny V. Cell, Vol. 162, Issue 6 https://doi.org/10.1016/j.cell.2015.08.041	journal	September 2015
Specification of Physiologic and Disease States by Distinct Proteins and Protein Conformations Jarosz, Daniel F.; Khurana, Vikram Cell, Vol. 171, Issue 5 https://doi.org/10.1016/j.cell.2017.10.047	journal	November 2017
Nuclear-Import Receptors Reverse Aberrant Phase Transitions of RNA-Binding Proteins with Prion-like Domains Guo, Lin; Kim, Hong Joo; Wang, Hejia Cell, Vol. 173, Issue 3 https://doi.org/10.1016/j.cell.2018.03.002	journal	April 2018
Inhibiting Stearoyl-CoA Desaturase Ameliorates α-Synuclein Cytotoxicity Vincent, Benjamin M.; Tardiff, Daniel F.; Piotrowski, Jeff S. Cell Reports, Vol. 25, Issue 10 https://doi.org/10.1016/j.celrep.2018.11.028	journal	December 2018
Mining Disaggregase Sequence Space to Safely Counter TDP-43, FUS, and α-Synuclein Proteotoxicity Tariq, Amber; Lin, JiaBei; Jackrel, Meredith E. Cell Reports, Vol. 28, Issue 8 https://doi.org/10.1016/j.celrep.2019.07.069	journal	August 2019
Genome-Scale Networks Link Neurodegenerative Disease Genes to α-Synuclein through Specific Molecular Pathways Khurana, Vikram; Peng, Jian; Chung, Chee Yeun Cell Systems, Vol. 4, Issue 2 https://doi.org/10.1016/j.cels.2016.12.011	journal	February 2017
Hsp104 Drives “Protein-Only” Positive Selection of Sup35 Prion Strains Encoding Strong [PSI+] DeSantis, Morgan E.; Shorter, James Chemistry & Biology, Vol. 19, Issue 11 https://doi.org/10.1016/j.chembiol.2012.09.013	journal	November 2012
Repurposing Hsp104 to Antagonize Seminal Amyloid and Counter HIV Infection Castellano, Laura M.; Bart, Stephen M.; Holmes, Veronica M. Chemistry & Biology, Vol. 22, Issue 8 https://doi.org/10.1016/j.chembiol.2015.07.007	journal	August 2015
The Glycolytic Enzyme, GPI, Is a Functionally Conserved Modifier of Dopaminergic Neurodegeneration in Parkinson’s Models Knight, Adam L.; Yan, Xiaohui; Hamamichi, Shusei Cell Metabolism, Vol. 20, Issue 1 https://doi.org/10.1016/j.cmet.2014.04.017	journal	July 2014
Designer protein disaggregases to counter neurodegenerative disease Shorter, James Current Opinion in Genetics & Development, Vol. 44 https://doi.org/10.1016/j.gde.2017.01.008	journal	June 2017
Mechanistic and Structural Insights into the Prion-Disaggregase Activity of Hsp104 Sweeny, Elizabeth A.; Shorter, James Journal of Molecular Biology, Vol. 428, Issue 9 https://doi.org/10.1016/j.jmb.2015.11.016	journal	May 2016
Destruction or Potentiation of Different Prions Catalyzed by Similar Hsp104 Remodeling Activities Shorter, James; Lindquist, Susan Molecular Cell, Vol. 23, Issue 3 https://doi.org/10.1016/j.molcel.2006.05.042	journal	August 2006
The Hsp104 N-Terminal Domain Enables Disaggregase Plasticity and Potentiation Sweeny, Elizabeth A.; Jackrel, Meredith E.; Go, Michelle S. Molecular Cell, Vol. 57, Issue 5 https://doi.org/10.1016/j.molcel.2014.12.021	journal	March 2015
Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment Fanning, Saranna; Haque, Aftabul; Imberdis, Thibaut Molecular Cell, Vol. 73, Issue 5 https://doi.org/10.1016/j.molcel.2018.11.028	journal	March 2019
ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97 Wang, Bo; Maxwell, Brian A.; Joo, Joung Hyuck Molecular Cell, Vol. 74, Issue 4 https://doi.org/10.1016/j.molcel.2019.03.027	journal	May 2019
Converging Mechanisms in ALS and FTD: Disrupted RNA and Protein Homeostasis Ling, Shuo-Chien; Polymenidou, Magdalini; Cleveland, Don W. Neuron, Vol. 79, Issue 3 https://doi.org/10.1016/j.neuron.2013.07.033	journal	August 2013
Parkinson’s Disease Genes VPS35 and EIF4G1 Interact Genetically and Converge on α-Synuclein Dhungel, Nripesh; Eleuteri, Simona; Li, Ling-bo Neuron, Vol. 85, Issue 1 https://doi.org/10.1016/j.neuron.2014.11.027	journal	January 2015
RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43 Mann, Jacob R.; Gleixner, Amanda M.; Mauna, Jocelyn C. Neuron, Vol. 102, Issue 2 https://doi.org/10.1016/j.neuron.2019.01.048	journal	April 2019
Structure of Calcarisporiella thermophila Hsp104 Disaggregase that Antagonizes Diverse Proteotoxic Misfolding Events Michalska, Karolina; Zhang, Kaiming; March, Zachary M. Structure, Vol. 27, Issue 3 https://doi.org/10.1016/j.str.2018.11.001	journal	March 2019
High-throughput protein purification and quality assessment for crystallization Kim, Youngchang; Babnigg, Gyorgy; Jedrzejczak, Robert Methods, Vol. 55, Issue 1 https://doi.org/10.1016/j.ymeth.2011.07.010	journal	September 2011
Hsp104, Hsp70, and Hsp40 Glover, John R.; Lindquist, Susan Cell, Vol. 94, Issue 1 https://doi.org/10.1016/s0092-8674(00)81223-4	journal	July 1998
Disparate Mutations Confer Therapeutic Gain of Hsp104 Function Jackrel, Meredith E.; Yee, Keolamau; Tariq, Amber ACS Chemical Biology, Vol. 10, Issue 12 https://doi.org/10.1021/acschembio.5b00765	journal	October 2015
Saccharomyces cerevisiae Hsp104 Enhances the Chaperone Capacity of Human Cells and Inhibits Heat Stress-Induced Proapoptotic Signaling ^† Mosser, Dick D.; Ho, Sylvia; Glover, John R. Biochemistry, Vol. 43, Issue 25 https://doi.org/10.1021/bi0493766	journal	June 2004
The C-terminal Extension of Saccharomyces cerevisiae Hsp104 Plays a Role in Oligomer Assembly ^† Mackay, Ryder G.; Helsen, Christopher W.; Tkach, Johnny M. Biochemistry, Vol. 47, Issue 7 https://doi.org/10.1021/bi701714s	journal	February 2008
Hspl04 is a highly conserved protein with two essential nucleotide-binding sites Parselt, Dawn A.; Sanchez, Yolanda; Stitzel, Joel D. Nature, Vol. 353, Issue 6341 https://doi.org/10.1038/353270a0	journal	September 1991
Protein disaggregation mediated by heat-shock protein Hspl04 Parsell, Dawn A.; Kowal, Anthony S.; Singer, Mike A. Nature, Vol. 372, Issue 6505 https://doi.org/10.1038/372475a0	journal	December 1994
α-Synuclein in Lewy bodies Spillantini, Maria Grazia; Schmidt, Marie Luise; Lee, Virginia M. -Y. Nature, Vol. 388, Issue 6645 https://doi.org/10.1038/42166	journal	August 1997
Yeast unfolds the road map toward α-synuclein-induced cell death Franssens, V.; Boelen, E.; Anandhakumar, J. Cell Death & Differentiation, Vol. 17, Issue 5 https://doi.org/10.1038/cdd.2009.203	journal	December 2009
Preservation of forelimb function by UPF1 gene therapy in a rat model of TDP-43-induced motor paralysis Jackson, K. L.; Dayton, R. D.; Orchard, E. A. Gene Therapy, Vol. 22, Issue 1 https://doi.org/10.1038/gt.2014.101	journal	November 2014
Fast, scalable generation of high‐quality protein multiple sequence alignments using Clustal Omega Sievers, Fabian; Wilm, Andreas; Dineen, David Molecular Systems Biology, Vol. 7, Issue 1 https://doi.org/10.1038/msb.2011.75	journal	January 2011
A newly discovered protein export machine in malaria parasites de Koning-Ward, Tania F.; Gilson, Paul R.; Boddey, Justin A. Nature, Vol. 459, Issue 7249 https://doi.org/10.1038/nature08104	journal	June 2009
Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS Elden, Andrew C.; Kim, Hyung-Jun; Hart, Michael P. Nature, Vol. 466, Issue 7310 https://doi.org/10.1038/nature09320	journal	August 2010
Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice Becker, Lindsay A.; Huang, Brenda; Bieri, Gregor Nature, Vol. 544, Issue 7650 https://doi.org/10.1038/nature22038	journal	April 2017
Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models Armakola, Maria; Higgins, Matthew J.; Figley, Matthew D. Nature Genetics, Vol. 44, Issue 12 https://doi.org/10.1038/ng.2434	journal	October 2012
Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models Kim, Hyung-Jun; Raphael, Alya R.; LaDow, Eva S. Nature Genetics, Vol. 46, Issue 2 https://doi.org/10.1038/ng.2853	journal	December 2013
α-Synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity Gitler, Aaron D.; Chesi, Alessandra; Geddie, Melissa L. Nature Genetics, Vol. 41, Issue 3 https://doi.org/10.1038/ng.300	journal	February 2009
High-efficiency yeast transformation using the LiAc/SS carrier DNA/PEG method Gietz, R. Daniel; Schiestl, Robert H. Nature Protocols, Vol. 2, Issue 1 https://doi.org/10.1038/nprot.2007.13	journal	January 2007
Cryptic genetic variation: evolution's hidden substrate Paaby, Annalise B.; Rockman, Matthew V. Nature Reviews Genetics, Vol. 15, Issue 4 https://doi.org/10.1038/nrg3688	journal	March 2014
A tightly regulated molecular toggle controls AAA+ disaggregase Oguchi, Yuki; Kummer, Eva; Seyffer, Fabian Nature Structural & Molecular Biology, Vol. 19, Issue 12 https://doi.org/10.1038/nsmb.2441	journal	November 2012
Spiral architecture of the Hsp104 disaggregase reveals the basis for polypeptide translocation Yokom, Adam L.; Gates, Stephanie N.; Jackrel, Meredith E. Nature Structural & Molecular Biology, Vol. 23, Issue 9 https://doi.org/10.1038/nsmb.3277	journal	August 2016
Structural basis for substrate gripping and translocation by the ClpB AAA+ disaggregase Rizo, Alexandrea N.; Lin, JiaBei; Gates, Stephanie N. Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-10150-y	journal	June 2019
Protein transmission in neurodegenerative disease Peng, Chao; Trojanowski, John Q.; Lee, Virginia M. -Y. Nature Reviews Neurology, Vol. 16, Issue 4 https://doi.org/10.1038/s41582-020-0333-7	journal	March 2020
Malaria parasite translocon structure and mechanism of effector export Ho, Chi-Min; Beck, Josh R.; Lai, Mason Nature, Vol. 561, Issue 7721 https://doi.org/10.1038/s41586-018-0469-4	journal	August 2018
Processive extrusion of polypeptide loops by a Hsp100 disaggregase Avellaneda, Mario J.; Franke, Kamila B.; Sunderlikova, Vanda Nature, Vol. 578, Issue 7794 https://doi.org/10.1038/s41586-020-1964-y	journal	January 2020
Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes Shahmoradian, Sarah H.; Lewis, Amanda J.; Genoud, Christel Nature Neuroscience, Vol. 22, Issue 7 https://doi.org/10.1038/s41593-019-0423-2	journal	June 2019
The Parkinson's disease protein -synuclein disrupts cellular Rab homeostasis Gitler, A. D.; Bevis, B. J.; Shorter, J. Proceedings of the National Academy of Sciences, Vol. 105, Issue 1 https://doi.org/10.1073/pnas.0710685105	journal	December 2007
Hypothesis-based RNAi screening identifies neuroprotective genes in a Parkinson's disease model Hamamichi, S.; Rivas, R. N.; Knight, A. L. Proceedings of the National Academy of Sciences, Vol. 105, Issue 2 https://doi.org/10.1073/pnas.0711018105	journal	January 2008
A yeast TDP-43 proteinopathy model: Exploring the molecular determinants of TDP-43 aggregation and cellular toxicity Johnson, B. S.; McCaffery, J. M.; Lindquist, S. Proceedings of the National Academy of Sciences, Vol. 105, Issue 17 https://doi.org/10.1073/pnas.0802082105	journal	April 2008
The pINDUCER lentiviral toolkit for inducible RNA interference in vitro and in vivo Meerbrey, Kristen L.; Hu, Guang; Kessler, Jessica D. Proceedings of the National Academy of Sciences, Vol. 108, Issue 9 https://doi.org/10.1073/pnas.1019736108	journal	February 2011
Species-specific collaboration of heat shock proteins (Hsp) 70 and 100 in thermotolerance and protein disaggregation Miot, M.; Reidy, M.; Doyle, S. M. Proceedings of the National Academy of Sciences, Vol. 108, Issue 17 https://doi.org/10.1073/pnas.1102828108	journal	April 2011
Calcineurin determines toxic versus beneficial responses to -synuclein Caraveo, G.; Auluck, P. K.; Whitesell, L. Proceedings of the National Academy of Sciences, Vol. 111, Issue 34 https://doi.org/10.1073/pnas.1413201111	journal	August 2014
Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1 Barmada, Sami J.; Ju, Shulin; Arjun, Arpana Proceedings of the National Academy of Sciences, Vol. 112, Issue 25 https://doi.org/10.1073/pnas.1509744112	journal	June 2015
Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington's disease Carmichael, J.; Chatellier, J.; Woolfson, A. Proceedings of the National Academy of Sciences, Vol. 97, Issue 17 https://doi.org/10.1073/pnas.170280697	journal	August 2000
FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome Caraveo, Gabriela; Soste, Martin; Cappelleti, Valentina Proceedings of the National Academy of Sciences, Vol. 114, Issue 52 https://doi.org/10.1073/pnas.1711926115	journal	December 2017
Stand-alone ClpG disaggregase confers superior heat tolerance to bacteria Lee, Changhan; Franke, Kamila B.; Kamal, Shady Mansour Proceedings of the National Academy of Sciences, Vol. 115, Issue 2 https://doi.org/10.1073/pnas.1712051115	journal	December 2017
Hydrogen exchange reveals Hsp104 architecture, structural dynamics, and energetics in physiological solution Ye, Xiang; Lin, Jiabei; Mayne, Leland Proceedings of the National Academy of Sciences, Vol. 116, Issue 15 https://doi.org/10.1073/pnas.1816184116	journal	March 2019
Parkinson’s disease is a type of amyloidosis featuring accumulation of amyloid fibrils of α-synuclein Araki, Katsuya; Yagi, Naoto; Aoyama, Koki Proceedings of the National Academy of Sciences, Vol. 116, Issue 36 https://doi.org/10.1073/pnas.1906124116	journal	August 2019
Structural and kinetic basis for the regulation and potentiation of Hsp104 function Ye, Xiang; Lin, JiaBei; Mayne, Leland Proceedings of the National Academy of Sciences, Vol. 117, Issue 17 https://doi.org/10.1073/pnas.1921968117	journal	April 2020
Analysis of the AAA sensor-2 motif in the C-terminal ATPase domain of Hsp104 with a site-specific fluorescent probe of nucleotide binding Hattendorf, D. A.; Lindquist, S. L. Proceedings of the National Academy of Sciences, Vol. 99, Issue 5 https://doi.org/10.1073/pnas.261693199	journal	February 2002
Subunit interactions influence the biochemical and biological properties of Hsp104 Schirmer, E. C.; Ware, D. M.; Queitsch, C. Proceedings of the National Academy of Sciences, Vol. 98, Issue 3 https://doi.org/10.1073/pnas.98.3.914	journal	January 2001
The ATPase Activity of Hsp104, Effects of Environmental Conditions and Mutations Schirmer, Eric C.; Queitsch, Christine; Kowal, Anthony S. Journal of Biological Chemistry, Vol. 273, Issue 25 https://doi.org/10.1074/jbc.273.25.15546	journal	June 1998
TDP-43 Is Intrinsically Aggregation-prone, and Amyotrophic Lateral Sclerosis-linked Mutations Accelerate Aggregation and Increase Toxicity Johnson, Brian S.; Snead, David; Lee, Jonathan J. Journal of Biological Chemistry, Vol. 284, Issue 30 https://doi.org/10.1074/jbc.M109.010264	journal	July 2009
Mammalian, Yeast, Bacterial, and Chemical Chaperones Reduce Aggregate Formation and Death in a Cell Model of Oculopharyngeal Muscular Dystrophy Bao, Yi Ping; Cook, Lynnette J.; O'Donovan, Dominic Journal of Biological Chemistry, Vol. 277, Issue 14 https://doi.org/10.1074/jbc.M109633200	journal	April 2002
Different 8-Hydroxyquinolines Protect Models of TDP-43 Protein, α-Synuclein, and Polyglutamine Proteotoxicity through Distinct Mechanisms Tardiff, Daniel F.; Tucci, Michelle L.; Caldwell, Kim A. Journal of Biological Chemistry, Vol. 287, Issue 6 https://doi.org/10.1074/jbc.M111.308668	journal	December 2011
Biosynthesis, Localization, and Macromolecular Arrangement of the Plasmodium falciparum Translocon of Exported Proteins (PTEX) Bullen, Hayley E.; Charnaud, Sarah C.; Kalanon, Ming Journal of Biological Chemistry, Vol. 287, Issue 11 https://doi.org/10.1074/jbc.M111.328591	journal	March 2012
Conserved Distal Loop Residues in the Hsp104 and ClpB Middle Domain Contact Nucleotide-binding Domain 2 and Enable Hsp70-dependent Protein Disaggregation DeSantis, Morgan E.; Sweeny, Elizabeth A.; Snead, David Journal of Biological Chemistry, Vol. 289, Issue 2 https://doi.org/10.1074/jbc.M113.520759	journal	January 2014
Mechanistic Insights into Hsp104 Potentiation Torrente, Mariana P.; Chuang, Edward; Noll, Megan M. Journal of Biological Chemistry, Vol. 291, Issue 10 https://doi.org/10.1074/jbc.M115.707976	journal	March 2016
Roles of Individual Domains and Conserved Motifs of the AAA+ Chaperone ClpB in Oligomerization, ATP Hydrolysis, and Chaperone Activity Mogk, Axel; Schlieker, Christian; Strub, Christine Journal of Biological Chemistry, Vol. 278, Issue 20 https://doi.org/10.1074/jbc.M209686200	journal	March 2003
Evidence for an Unfolding/Threading Mechanism for Protein Disaggregation by Saccharomyces cerevisiae Hsp104 Lum, Ronnie; Tkach, Johnny M.; Vierling, Elizabeth Journal of Biological Chemistry, Vol. 279, Issue 28 https://doi.org/10.1074/jbc.M403777200	journal	May 2004
A Chaperone Pathway in Protein Disaggregation Cashikar, Anil G.; Duennwald, Martin; Lindquist, Susan L. Journal of Biological Chemistry, Vol. 280, Issue 25 https://doi.org/10.1074/jbc.M502854200	journal	June 2005
Disturbance of Nuclear and Cytoplasmic TAR DNA-binding Protein (TDP-43) Induces Disease-like Redistribution, Sequestration, and Aggregate Formation Winton, Matthew J.; Igaz, Lionel M.; Wong, Margaret M. Journal of Biological Chemistry, Vol. 283, Issue 19 https://doi.org/10.1074/jbc.M800342200	journal	May 2008
Peptide and Protein Binding in the Axial Channel of Hsp104: INSIGHTS INTO THE MECHANISM OF PROTEIN UNFOLDING Lum, Ronnie; Niggemann, Monika; Glover, John R. Journal of Biological Chemistry, Vol. 283, Issue 44 https://doi.org/10.1074/jbc.M804849200	journal	August 2008
Engineered protein disaggregases mitigate toxicity of aberrant prion-like fusion proteins underlying sarcoma Ryan, Jeremy J.; Sprunger, Macy L.; Holthaus, Kayla Journal of Biological Chemistry, Vol. 294, Issue 29 https://doi.org/10.1074/jbc.RA119.009494	journal	July 2019
Structural and mechanistic insights into Hsp104 function revealed by synchrotron X-ray footprinting Sweeny, Elizabeth A.; Tariq, Amber; Gurpinar, Esin Journal of Biological Chemistry, Vol. 295, Issue 6 https://doi.org/10.1074/jbc.RA119.011577	journal	December 2019
Engineering enhanced protein disaggregases for neurodegenerative disease Jackrel, Meredith E.; Shorter, James Prion, Vol. 9, Issue 2 https://doi.org/10.1080/19336896.2015.1020277	journal	March 2015
FUS inclusions disrupt RNA localization by sequestering kinesin-1 and inhibiting microtubule detyrosination Yasuda, Kyota; Clatterbuck-Soper, Sarah F.; Jackrel, Meredith E. Journal of Cell Biology, Vol. 216, Issue 4 https://doi.org/10.1083/jcb.201608022	journal	March 2017
Dominant Gain-of-Function Mutations in Hsp104p Reveal Crucial Roles for the Middle Region Schirmer, Eric C.; Homann, Oliver R.; Kowal, Anthony S. Molecular Biology of the Cell, Vol. 15, Issue 5 https://doi.org/10.1091/mbc.e02-08-0502	journal	May 2004
α-Synuclein–induced Aggregation of Cytoplasmic Vesicles in Saccharomyces cerevisiae Soper, James H.; Roy, Subhojit; Stieber, Anna Molecular Biology of the Cell, Vol. 19, Issue 3 https://doi.org/10.1091/mbc.e07-08-0827	journal	March 2008
Jalview Version 2--a multiple sequence alignment editor and analysis workbench Waterhouse, A. M.; Procter, J. B.; Martin, D. M. A. Bioinformatics, Vol. 25, Issue 9 https://doi.org/10.1093/bioinformatics/btp033	journal	January 2009
Identification of thermolabile Escherichia coli proteins: prevention and reversion of aggregation by DnaK and ClpB Mogk, A. The EMBO Journal, Vol. 18, Issue 24 https://doi.org/10.1093/emboj/18.24.6934	journal	December 1999
Potentiating Hsp104 activity via phosphomimetic mutations in the middle domain Tariq, Amber; Lin, JiaBei; Noll, Megan M. FEMS Yeast Research, Vol. 18, Issue 5 https://doi.org/10.1093/femsyr/foy042	journal	April 2018
THE GENETICS OF CAENORHABDITIS ELEGANS Brenner, S. Genetics, Vol. 77, Issue 1 https://doi.org/10.1093/genetics/77.1.71	journal	May 1974
Overexpression of yeast hsp104 reduces polyglutamine aggregation and prolongs survival of a transgenic mouse model of Huntington's disease Vacher, Coralie; Garcia-Oroz, Lourdes; Rubinsztein, David C. Human Molecular Genetics, Vol. 14, Issue 22 https://doi.org/10.1093/hmg/ddi372	journal	October 2005
TimeTree: A Resource for Timelines, Timetrees, and Divergence Times Kumar, Sudhir; Stecher, Glen; Suleski, Michael Molecular Biology and Evolution, Vol. 34, Issue 7 https://doi.org/10.1093/molbev/msx116	journal	April 2017
The EMBL-EBI search and sequence analysis tools APIs in 2019 Madeira, Fábio; Park, Young mi; Lee, Joon Nucleic Acids Research, Vol. 47, Issue W1 https://doi.org/10.1093/nar/gkz268	journal	April 2019
Spiraling in Control: Structures and Mechanisms of the Hsp104 Disaggregase Shorter, James; Southworth, Daniel R. Cold Spring Harbor Perspectives in Biology, Vol. 11, Issue 8 https://doi.org/10.1101/cshperspect.a034033	journal	February 2019
Heat Shock Protein 101 Plays a Crucial Role in Thermotolerance in Arabidopsis Queitsch, Christine; Hong, Suk-Whan; Vierling, Elizabeth The Plant Cell, Vol. 12, Issue 4 https://doi.org/10.1105/tpc.12.4.479	journal	April 2000
Substrate threading through the central pore of the Hsp104 chaperone as a common mechanism for protein disaggregation and prion propagation Tessarz, Peter; Mogk, Axel; Bukau, Bernd Molecular Microbiology, Vol. 68, Issue 1 https://doi.org/10.1111/j.1365-2958.2008.06135.x	journal	April 2008
Characterization of α-synuclein aggregation and synergistic toxicity with protein tau in yeast: Aggregation of α-synuclein in yeast cells Zabrocki, Piotr; Pellens, Klaartje; Vanhelmont, Thomas FEBS Journal, Vol. 272, Issue 6 https://doi.org/10.1111/j.1742-4658.2005.04571.x	journal	March 2005
Yeast Cells Provide Insight into Alpha-Synuclein Biology and Pathobiology Outeiro, T. F. Science, Vol. 302, Issue 5651 https://doi.org/10.1126/science.1090439	journal	December 2003
Hsp104 Catalyzes Formation and Elimination of Self-Replicating Sup35 Prion Conformers Shorter, J. Science, Vol. 304, Issue 5678 https://doi.org/10.1126/science.1098007	journal	June 2004
-Synuclein Blocks ER-Golgi Traffic and Rab1 Rescues Neuron Loss in Parkinson's Models Cooper, A. A. Science, Vol. 313, Issue 5785 https://doi.org/10.1126/science.1129462	journal	July 2006
Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis Neumann, M.; Sampathu, D. M.; Kwong, L. K. Science, Vol. 314, Issue 5796 https://doi.org/10.1126/science.1134108	journal	October 2006
Identification and Rescue of -Synuclein Toxicity in Parkinson Patient-Derived Neurons Chung, C. Y.; Khurana, V.; Auluck, P. K. Science, Vol. 342, Issue 6161 https://doi.org/10.1126/science.1245296	journal	October 2013
Yeast Reveal a "Druggable" Rsp5/Nedd4 Network that Ameliorates -Synuclein Toxicity in Neurons Tardiff, D. F.; Jui, N. T.; Khurana, V. Science, Vol. 342, Issue 6161 https://doi.org/10.1126/science.1245321	journal	October 2013
HSP104 required for induced thermotolerance Sanchez, Y.; Lindquist, S. Science, Vol. 248, Issue 4959 https://doi.org/10.1126/science.2188365	journal	June 1990
Ratchet-like polypeptide translocation mechanism of the AAA+ disaggregase Hsp104 Gates, Stephanie N.; Yokom, Adam L.; Lin, JiaBei Science, Vol. 357, Issue 6348 https://doi.org/10.1126/science.aan1052	journal	June 2017
Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau Darwich, Nabil F.; Phan, Jessica M.; Kim, Boram Science, Vol. 370, Issue 6519 https://doi.org/10.1126/science.aay8826	journal	October 2020
Beyond aggregation: Pathological phase transitions in neurodegenerative disease Mathieu, Cécile; Pappu, Rohit V.; Taylor, J. Paul Science, Vol. 370, Issue 6512 https://doi.org/10.1126/science.abb8032	journal	October 2020
Applying Hsp104 to protein-misfolding disordersThis paper is one of a selection of papers published in this special issue entitled 8th International Conference on AAA Proteins and has undergone the Journal's usual peer review process. Vashist, Shilpa; Cushman, Mimi; Shorter, James Biochemistry and Cell Biology, Vol. 88, Issue 1 https://doi.org/10.1139/o09-121	journal	February 2010
Hsp104: A Weapon to Combat Diverse Neurodegenerative Disorders Shorter, James Neurosignals, Vol. 16, Issue 1 https://doi.org/10.1159/000109760	journal	December 2007
Hsp104 antagonizes α-synuclein aggregation and reduces dopaminergic degeneration in a rat model of Parkinson disease Lo Bianco, Christophe; Shorter, James; Régulier, Etienne Journal of Clinical Investigation, Vol. 118, Issue 9 https://doi.org/10.1172/JCI35781	journal	September 2008
Alpha-synuclein biology in Lewy body diseases Kim, Woojin Scott; Kågedal, Katarina; Halliday, Glenda M. Alzheimer's Research & Therapy, Vol. 6, Issue 5-8 https://doi.org/10.1186/s13195-014-0073-2	journal	October 2014
Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson's disease models Su, L. J.; Auluck, P. K.; Outeiro, T. F. Disease Models & Mechanisms, Vol. 3, Issue 3-4 https://doi.org/10.1242/dmm.004267	journal	December 2009
Potentiated Hsp104 variants suppress toxicity of diverse neurodegenerative disease-linked proteins Jackrel, M. E.; Shorter, J. Disease Models & Mechanisms, Vol. 7, Issue 10 https://doi.org/10.1242/dmm.016113	journal	July 2014
Amyloid assembly and disassembly Chuang, Edward; Hori, Acacia M.; Hesketh, Christina D. Journal of Cell Science, Vol. 131, Issue 8 https://doi.org/10.1242/jcs.189928	journal	April 2018
Molecular Determinants and Genetic Modifiers of Aggregation and Toxicity for the ALS Disease Protein FUS/TLS Sun, Zhihui; Diaz, Zamia; Fang, Xiaodong PLoS Biology, Vol. 9, Issue 4 https://doi.org/10.1371/journal.pbio.1000614	journal	April 2011
A Yeast Model of FUS/TLS-Dependent Cytotoxicity Ju, Shulin; Tardiff, Daniel F.; Han, Haesun PLoS Biology, Vol. 9, Issue 4 https://doi.org/10.1371/journal.pbio.1001052	journal	April 2011
A speed–fidelity trade-off determines the mutation rate and virulence of an RNA virus Fitzsimmons, William J.; Woods, Robert J.; McCrone, John T. PLOS Biology, Vol. 16, Issue 6 https://doi.org/10.1371/journal.pbio.2006459	journal	June 2018
Hsp104 Suppresses Polyglutamine-Induced Degeneration Post Onset in a Drosophila MJD/SCA3 Model Cushman-Nick, Mimi; Bonini, Nancy M.; Shorter, James PLoS Genetics, Vol. 9, Issue 9 https://doi.org/10.1371/journal.pgen.1003781	journal	September 2013
Phosphorylation Modulates Clearance of Alpha-Synuclein Inclusions in a Yeast Model of Parkinson's Disease Tenreiro, Sandra; Reimão-Pinto, Madalena M.; Antas, Pedro PLoS Genetics, Vol. 10, Issue 5 https://doi.org/10.1371/journal.pgen.1004302	journal	May 2014
The Mammalian Disaggregase Machinery: Hsp110 Synergizes with Hsp70 and Hsp40 to Catalyze Protein Disaggregation and Reactivation in a Cell-Free System Shorter, James PLoS ONE, Vol. 6, Issue 10 https://doi.org/10.1371/journal.pone.0026319	journal	October 2011
Metabolic and Chaperone Gene Loss Marks the Origin of Animals: Evidence for Hsp104 and Hsp78 Chaperones Sharing Mitochondrial Enzymes as Clients Erives, Albert J.; Fassler, Jan S. PLOS ONE, Vol. 10, Issue 2 https://doi.org/10.1371/journal.pone.0117192	journal	February 2015
Prime Time for -Synuclein Gitler, A. D.; Shorter, J. Journal of Neuroscience, Vol. 27, Issue 10 https://doi.org/10.1523/JNEUROSCI.0094-07.2007	journal	March 2007
Torsin-Mediated Protection from Cellular Stress in the Dopaminergic Neurons of Caenorhabditis elegans Cao, S. Journal of Neuroscience, Vol. 25, Issue 15 https://doi.org/10.1523/JNEUROSCI.5157-04.2005	journal	April 2005
Alpha-synuclein spreading in Parkinsonâ€™s disease Recasens, Ariadna; Dehay, Benjamin Frontiers in Neuroanatomy, Vol. 8 https://doi.org/10.3389/fnana.2014.00159	journal	December 2014
Features of alpha-synuclein that could explain the progression and irreversibility of Parkinson's disease Gallegos, Scarlet; Pacheco, Carla; Peters, Christian Frontiers in Neuroscience, Vol. 9 https://doi.org/10.3389/fnins.2015.00059	journal	March 2015
ClpG Provides Increased Heat Resistance by Acting as Superior Disaggregase Katikaridis, Panagiotis; Meins, Lena; Kamal, Shady Mansour Biomolecules, Vol. 9, Issue 12 https://doi.org/10.3390/biom9120815	journal	December 2019
Generation of Stable Transgenic C. elegans Using Microinjection Berkowitz, Laura A.; Knight, Adam L.; Caldwell, Guy A. Journal of Visualized Experiments, Issue 18 https://doi.org/10.3791/833	journal	January 2008
RNA-binding proteins with prion-like domains in ALS and FTLD-U Gitler, Aaron D.; Shorter, James Prion, Vol. 5, Issue 3 https://doi.org/10.4161/pri.5.3.17230	journal	July 2011
Alpha-Synuclein Function and Dysfunction on Cellular Membranes Snead, David; Eliezer, David Experimental Neurobiology, Vol. 23, Issue 4 https://doi.org/10.5607/en.2014.23.4.292	journal	December 2014
Skd3 (human ClpB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations Cupo, Ryan R.; Shorter, James eLife, Vol. 9 https://doi.org/10.7554/eLife.55279	journal	June 2020

Similar Records

Structure of Calcarisporiella thermophila Hsp104 Disaggregase that Antagonizes Diverse Proteotoxic Misfolding Events

Journal Article · Wed Dec 26 19:00:00 EST 2018 · Structure · OSTI ID:1506849

Overlapping and Specific Functions of the Hsp104 N Domain Define Its Role in Protein Disaggregation

Journal Article · Sun Sep 10 20:00:00 EDT 2017 · Scientific Reports · OSTI ID:1393583

Related Subjects

59 BASIC BIOLOGICAL SCIENCES

Therapeutic genetic variation revealed in diverse Hsp104 homologs

Citation Formats

References (134)

Similar Records

Related Subjects