A Chaperome Subnetwork Safeguards Proteostasis in Aging and Neurodegenerative Disease

Abstract

SUMMARY 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.

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

“…Other predisposing factors can markedly elevate the risk of specific neurological diseases, for example, brain trauma, epilepsy, hypertension, obesity, type 2 diabetes, and exposure to toxic chemicals (in AD, PD) (Vosler et al ., 2008; Zigman, 2013). Age is a major risk factor for almost all neuropathies, as well as an important determinant of disease progression (Brehme et al ., 2014; Fjell et al ., 2014). …”

Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

“…This protein homeostasis system is comprised of a variety of components, including molecular chaperones, the proteolytic, ubiquitin-proteasome and autophagic degradation pathways, cellular trafficking, and other elements of the cellular stress response (3)(4)(5)(6)(21)(22)(23)(24)(25)(26). The progressive decline of the efficacy of these regulatory processes upon aging is likely to contribute to the increased susceptibility of the elderly population to ageassociated neurodegenerative disorders (3)(4)(5)(6)(21)(22)(23)(24)(25)(26)(27)(28).…”

“…Given the intrinsic propensity of proteins to aggregate, it is not surprising that we are endowed with a powerful array of defense mechanisms whose role is to preserve protein homeostasis by helping to maintain proteins in their soluble states and to promote the degradation of those that misfold and aggregate (3)(4)(5)(6)(21)(22)(23)(24)(25). This protein homeostasis system is comprised of a variety of components, including molecular chaperones, the proteolytic, ubiquitin-proteasome and autophagic degradation pathways, cellular trafficking, and other elements of the cellular stress response (3)(4)(5)(6)(21)(22)(23)(24)(25)(26).…”

Molecular chaperones and neuronal proteostasis

“…Aging is considered the most significant risk factor for sporadic cases of ALS, AD and PD. It is well established that aging results in a decline in the efficiency of the protein quality control machinery [11], although the cause for this decline is currently unknown. The age-associated decline in protein quality control has been suggested to lead to an imbalance in the production of misfolded protein, which slowly overwhelms the protective capacity of the molecular chaperone machinery, ultimately leading to a vicious cycle which results in the collapse of proteostasis and causes neurodegeneration [2].…”