title: A chaperome subnetwork safeguards proteostasis in aging and neurodegenerative disease.
abstract: Chaperones are central to the proteostasis network (PN) and safeguard the proteome from misfolding, aggregation, and proteotoxicity. We categorized the human chaperome of 332 genes into network communities using function, localization, interactome, and expression data sets. During human brain aging, expression of 32% of the chaperome, corresponding to ATP-dependent chaperone machines, is repressed, whereas 19.5%, corresponding to ATP-independent chaperones and co-chaperones, are induced. These repression and induction clusters are enhanced in the brains of those with Alzheimer's, Huntington's, or Parkinson's disease. Functional properties of the chaperome were assessed by perturbation in C. elegans and human cell models expressing Aβ, polyglutamine, and Huntingtin. Of 219 C. elegans orthologs, knockdown of 16 enhanced both Aβ and polyQ-associated toxicity. These correspond to 28 human orthologs, of which 52% and 41% are repressed, respectively, in brain aging and disease and 37.5% affected Huntingtin aggregation in human cells. These results identify a critical chaperome subnetwork that functions in aging and disease.
authors.affiliation: Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Brehme
authors.affiliation: Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Voisine
authors.affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rolland
authors.affiliation: Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Wachi
authors.affiliation: Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Soper
authors.affiliation: Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA.
authors.forename: Yitan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Orton
authors.affiliation: Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Villella
authors.affiliation: Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Garza
authors.affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: marc_vidal@dfci.harvard.edu.
authors.forename: Marc
authors.initials: M
authors.lastname: Vidal
authors.affiliation: Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA. Electronic address: hui.ge@novartis.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Ge
authors.affiliation: Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA. Electronic address: r-morimoto@northwestern.edu.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D017173:Caenorhabditis elegans / Q000254:growth & development / Q000378:metabolism; D004195:Disease Models, Animal; D053263:Gene Regulatory Networks; D006801:Humans; D000071058:Huntingtin Protein; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000150:complications* / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000378:metabolism; D017510:Protein Folding; D057165:Proteostasis Deficiencies / Q000150:complications* / Q000378:metabolism*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins