Therapeutic genetic variation revealed in diverse Hsp104 homologs
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. Her...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/57457 |
| _version_ | 1811201388350275584 |
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| author | Zachary M March Katelyn Sweeney Hanna Kim Xiaohui Yan Laura M Castellano Meredith E Jackrel JiaBei Lin Edward Chuang Edward Gomes Corey W Willicott Karolina Michalska Robert P Jedrzejczak Andrzej Joachimiak Kim A Caldwell Guy A Caldwell Ophir Shalem James Shorter |
| author_facet | Zachary M March Katelyn Sweeney Hanna Kim Xiaohui Yan Laura M Castellano Meredith E Jackrel JiaBei Lin Edward Chuang Edward Gomes Corey W Willicott Karolina Michalska Robert P Jedrzejczak Andrzej Joachimiak Kim A Caldwell Guy A Caldwell Ophir Shalem James Shorter |
| author_sort | Zachary M March |
| collection | DOAJ |
| description | 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. 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. |
| first_indexed | 2024-04-12T02:19:58Z |
| format | Article |
| id | doaj.art-662872aaafe84e1eaa7ff92be7d2d799 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:19:58Z |
| publishDate | 2020-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-662872aaafe84e1eaa7ff92be7d2d7992022-12-22T03:52:08ZengeLife Sciences Publications LtdeLife2050-084X2020-12-01910.7554/eLife.57457Therapeutic genetic variation revealed in diverse Hsp104 homologsZachary M March0https://orcid.org/0000-0003-2441-899XKatelyn Sweeney1Hanna Kim2Xiaohui Yan3Laura M Castellano4Meredith E Jackrel5https://orcid.org/0000-0003-4406-9504JiaBei Lin6Edward Chuang7Edward Gomes8Corey W Willicott9Karolina Michalska10Robert P Jedrzejczak11Andrzej Joachimiak12Kim A Caldwell13https://orcid.org/0000-0003-1580-6122Guy A Caldwell14Ophir Shalem15James Shorter16https://orcid.org/0000-0001-5269-8533Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States; Department of Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United StatesDepartment of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States; Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, United StatesDepartment of Biological Sciences, The University of Alabama, Tuscaloosa, United StatesDepartment of Biological Sciences, The University of Alabama, Tuscaloosa, United StatesDepartment of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States; Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United StatesDepartment of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United StatesDepartment of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United StatesDepartment of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States; Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United StatesDepartment of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United StatesDepartment of Biological Sciences, The University of Alabama, Tuscaloosa, United StatesStructural Biology Center, X-ray Science Division, Argonne National Laboratory, Argonne, United States; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, United StatesStructural Biology Center, X-ray Science Division, Argonne National Laboratory, Argonne, United StatesStructural Biology Center, X-ray Science Division, Argonne National Laboratory, Argonne, United States; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, United StatesDepartment of Biological Sciences, The University of Alabama, Tuscaloosa, United StatesDepartment of Biological Sciences, The University of Alabama, Tuscaloosa, United StatesDepartment of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States; Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, United StatesDepartment of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States; Department of Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States; Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United StatesThe 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. 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.https://elifesciences.org/articles/57457disaggregasechaperoneHsp104protein misfoldingTDP-43alpha-synuclein |
| spellingShingle | Zachary M March Katelyn Sweeney Hanna Kim Xiaohui Yan Laura M Castellano Meredith E Jackrel JiaBei Lin Edward Chuang Edward Gomes Corey W Willicott Karolina Michalska Robert P Jedrzejczak Andrzej Joachimiak Kim A Caldwell Guy A Caldwell Ophir Shalem James Shorter Therapeutic genetic variation revealed in diverse Hsp104 homologs eLife disaggregase chaperone Hsp104 protein misfolding TDP-43 alpha-synuclein |
| title | Therapeutic genetic variation revealed in diverse Hsp104 homologs |
| title_full | Therapeutic genetic variation revealed in diverse Hsp104 homologs |
| title_fullStr | Therapeutic genetic variation revealed in diverse Hsp104 homologs |
| title_full_unstemmed | Therapeutic genetic variation revealed in diverse Hsp104 homologs |
| title_short | Therapeutic genetic variation revealed in diverse Hsp104 homologs |
| title_sort | therapeutic genetic variation revealed in diverse hsp104 homologs |
| topic | disaggregase chaperone Hsp104 protein misfolding TDP-43 alpha-synuclein |
| url | https://elifesciences.org/articles/57457 |
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