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

• Published in: Cell reports (Cambridge) Vol. 9; no. 3; pp. 1135 - 1150
• Main Authors: Brehme, Marc, Voisine, Cindy, Rolland, Thomas, Wachi, Shinichiro, Soper, James H, Zhu, Yitan, Orton, Kai, Villella, Adriana, Garza, Dan, Vidal, Marc, Ge, Hui, Morimoto, Richard I
• Format: Journal Article
• Language: English
• Published: 23.10.2014
• ISSN: 2211-1247
• DOI: 10.1016/j.celrep.2014.09.042

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.