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Review
. 2021 Dec;159(6):958-979.
doi: 10.1111/jnc.15525. Epub 2021 Oct 31.

The penalty of stress - Epichaperomes negatively reshaping the brain in neurodegenerative disorders

Stephen D Ginsberg  1   2 , Suhasini Joshi  3 , Sahil Sharma  3 , Gianny Guzman  3 , Tai Wang  3 , Ottavio Arancio  4   5 , Gabriela Chiosis  3   6
Affiliations
Review

The penalty of stress - Epichaperomes negatively reshaping the brain in neurodegenerative disorders

Stephen D Ginsberg et al. J Neurochem. 2021 Dec.

Abstract

Adaptation to acute and chronic stress and/or persistent stressors is a subject of wide interest in central nervous system disorders. In this context, stress is an effector of change in organismal homeostasis and the response is generated when the brain perceives a potential threat. Herein, we discuss a nuanced and granular view whereby a wide variety of genotoxic and environmental stressors, including aging, genetic risk factors, environmental exposures, and age- and lifestyle-related changes, act as direct insults to cellular, as opposed to organismal, homeostasis. These two concepts of how stressors impact the central nervous system are not mutually exclusive. We discuss how maladaptive stressor-induced changes in protein connectivity through epichaperomes, disease-associated pathologic scaffolds composed of tightly bound chaperones, co-chaperones, and other factors, impact intracellular protein functionality altering phenotypes, that in turn disrupt and remodel brain networks ranging from intercellular to brain connectome levels. We provide an evidence-based view on how these maladaptive changes ranging from stressor to phenotype provide unique precision medicine opportunities for diagnostic and therapeutic development, especially in the context of neurodegenerative disorders including Alzheimer's disease where treatment options are currently limited.

Keywords: Alzheimer's disease; chronic stress and stressors; epichaperomes; maladaptive response to stress; stressor-to-phenotype; synaptic plasticity.

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Conflict of interest statement

CONFLICT OF INTEREST

Memorial Sloan Kettering Cancer Center holds the intellectual rights to PU-H71 and PU-AD. Samus Therapeutics Inc, of which G.C. has partial ownership, and is a member of its board of directors, has licensed this portfolio. G.C. is an inventor on the licensed intellectual property. All other authors declare no competing interests.

Figures

FIGURE 1
FIGURE 1
Biochemical (a) and functional (b, c) distinction between chaperones and epichaperomes. There is a fundamental structural, dynamic, and functional difference between HSP90 and HSP90 incorporated into an epichaperome. Epichaperomes are scaffolds. They rewire the connectivity and function of protein networks by remodeling how thousands of proteins interact in conditions of chronic cellular stress. Conversely, HSP90 is a chaperone. Chaperones, co-chaperones, and their complexes have defined functions as protein folders. They interact with a protein to process it through the chaperone folding cycle. Epichaperomes are long-lived oligomers of chaperome members. This differs from chaperones such as HSP90, which interact in a highly dynamic manner with one another and with client proteins on the millisecond to second timescale to make folding versus degradation decisions through transient interactions within the context of the proteostasis network. Epichaperomes are specific to cells exposed to defined stressors and/or combination of stressors. Conversely, chaperones are highly abundant and ubiquitous proteins. Epichaperome composition is stressor specific with distinct epichaperome assemblies impacting specific proteins, and in turn, protein pathways. Therefore, epichaperomes are multimeric, long-lived chaperome structures that act as scaffold for remodeling PPIs and provide a link between stressor-induced protein–protein interaction network perturbations and phenotypes. Abbreviations: HSP90, heat shock protein 90 (HSP90α and HSP90β isoforms, encoded by the HSP90AA1 and HSP90AB1 genes, respectively; HSC70, heat shock cognate 70 protein encoded by the HSPA8 gene; PPIs, protein–protein interactions
FIGURE 2
FIGURE 2
Stressor-to-phenotype assessments via epichaperomics, the omics method that uses epichaperomes to identify and study aberrant PPIs in disease. (a) Schematic showing epichaperomics sample analysis and data processing. (b) Unsupervised clustering of datasets from Inda et al. (2020). Human brains (sporadic late-onset AD, n = 5 vs NCI = 3). (c) Reactome mapping of proteins in each of the three major clusters. In the Reactome map, generated in Cytoscape, each circle represents a function (i.e., a protein pathway). If the circle is divided among gray, red, and teal, it means the dysfunction in the particular protein pathway is characteristic of each cluster. (d) Schematic showing how the accumulation of stressors during the disease spectrum can negatively impact PPI to cascade in impaired cellular activity, intra-cellular communication, brain region connectivity, ultimately leading to decline seen in these disorders, such as AD. Abbreviations: AD, Alzheimer’s disease; NCI, no cognitive impairment
FIGURE 3
FIGURE 3
Chemical structure of epichaperome inhibitors and epichaperome detection probes (a) and the biochemical mechanism for their selective binding to HSP90-incorporated into epichaperomes over the abundant and ubiquitously expressed HSP90 chaperone pool, and for their restorative effect on cellular function (b). Abbreviations: Koff, dissociation rate constant
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