A Chaperome Sub-Network Safeguards Proteostasis in Aging and Neurodegenerative Disease

Marc Brehme; Cindy Voisine; Thomas Rolland; Shinichiro Wachi; James H Soper; Yitan Zhu; Kai Orton; Adriana Villella; Dan Garza; Marc Vidal; Hui Ge; Richard I Morimoto

doi:10.1016/j.celrep.2014.09.042

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A Chaperome Sub-Network Safeguards Proteostasis in Aging and Neurodegenerative Disease

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A Chaperome Sub-Network Safeguards Proteostasis in Aging and Neurodegenerative Disease

Marc Brehme, Cindy Voisine, Thomas Rolland, Shinichiro Wachi, James H Soper, Yitan Zhu, Kai Orton, Adriana Villella, Dan Garza, Marc Vidal, …

Cell reports (Cambridge), Vol.9(3), pp.1135-1150

23/10/2014

DOI: https://doi.org/10.1016/j.celrep.2014.09.042

PMID: 25437566

Résumé

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 datasets. 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 Alzheimer's, Huntington's, and Parkinson's brains. 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 sixteen 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 sub-network that functions in aging and disease.

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Détails

Titre: A Chaperome Sub-Network Safeguards Proteostasis in Aging and Neurodegenerative Disease
Créateurs - sans rôle: Marc Brehme - Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA Center for Cancer Systems Biology, 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
Cindy Voisine - Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA Center for Cancer Systems Biology, 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
Thomas Rolland - Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA Center for Cancer Systems Biology, 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
Shinichiro Wachi - Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA Center for Cancer Systems Biology, 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
James H Soper - Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA Center for Cancer Systems Biology, 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
Yitan Zhu - Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA Center for Cancer Systems Biology, 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
Kai Orton - Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA Center for Cancer Systems Biology, 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
Adriana Villella - Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA Center for Cancer Systems Biology, 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
Dan Garza - Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA Center for Cancer Systems Biology, 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
Marc Vidal - Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA Center for Cancer Systems Biology, 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
Hui Ge - Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA Center for Cancer Systems Biology, 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
Richard I Morimoto - Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA Center for Cancer Systems Biology, 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
Détails de publication: Cell reports (Cambridge), Vol.9(3), pp.1135-1150
Identifiants: 99149619909311
Unité académique: Centre de Recherche en Biologie Cellulaire de Montpellier - CRBM
Langue: English
Type de ressource: Journal article