Disease‐specific interactome alterations via epichaperomics: the case for Alzheimer’s disease

Abstract

The increasingly appreciated prevalence of complicated stressor-to-phenotype associations in human disease requires a greater understanding of how specific stressors affect systems or interactome properties. Many currently untreatable diseases arise due to variations in, and through a combination of, multiple stressors of genetic, epigenetic, and environmental nature.Unfortunately, how such stressors lead to a specific disease phenotype or inflict a vulnerability to some cells and tissues but not others, remains largely unknown and unsatisfactorily addressed.Analysis of cell-and tissue-specific interactome networks may shed light on organization of biological systems and subsequently to disease vulnerabilities. However, deriving human interactomes across different cell-and disease-contexts remains a challenge. To this end, this opinion article links stressor-induced protein interactome network perturbations to the formation of pathologic scaffolds termed epichaperomes, revealing a viable and reproducible experimental solution to obtaining rigorous context-dependent interactomes. This article presents our views on how a specialized 'omics platform called epichaperomics may complement and enhance the currently available conventional approaches and aid the scientific community in defining, understanding, and ultimately controlling interactome networks of complex diseases such as Alzheimer's disease. Ultimately, this approach may aid the transition from a limited single-alteration perspective in disease to a comprehensive network-based mindset, which we posit will result in precision medicine paradigms for disease diagnosis and treatment.

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

“…The observed vulnerability of synaptic function to stressors is not surprising because of the critical involvement of this pathway in a number of neurological conditions, such as neurodegenerative diseases (e.g., AD, PD, and Huntington's disease, among others), neurodevelopmental disorders (e.g., autism and Down syndrome), as well as neuropsychiatric disorders (e.g., bipolar disorder, major depressive disorder, and schizophrenia) (Compta & Revesz, 2021;Counts et al, 2014;Eltokhi et al, 2021;Garner & Wetmore, 2012;Ginsberg et al, 2012;Henstridge et al, 2016). Each of these distinct disorders may arise because of perturbation in, and via a combination of, a multiplicity of genetic, epigenetic, and environmental stressors, which we posit can be interrogated by epichaperomics (Ginsberg et al, 2021).…”

“…The first glimpse into proteins negatively impacted by epichaperome formation comes from cancer where Moulick and coworkers found epichaperome interactomes contained multiple proteins as part of megacomplexes rather than single proteins (Moulick et al, 2011). This finding led to the hypothesis that epichaperome formation may in fact act as a scaffolding platform and lead to formation of maladaptive PPIs in cells exposed to stressors (Ginsberg et al, 2021;Joshi et al, 2018). This postulate was confirmed in a variety of disease settings and disease models (Inda et al, 2020;Kishinevsky et al, 2018).…”

“…Functionally, epichaperomes are also distinct from chaperones as they act as scaffolds for remodeling PPIs at the proteome-wide level, rather than folders of proteins in protein synthesis and degradation pathways (Figure 1b) (Ginsberg et al, 2021;Inda et al, 2020;Joshi et al, 2018;Kishinevsky et al, 2018;Yan et al, 2020). A first glimpse into this role comes from a large-scale unbiased approach conducted by Moulick and coworkers that interrogated the interactome of HSP90-incorporating epichaperomes in the K562 chronic myeloid leukemia cells (Moulick et al, 2011).…”

“…Remarkably, a commonality of distinct stressors was a profound impact on PPIs related to synaptic plasticity including a genetic stressor (APP duplication) in iPSC-derived neurons, and proteotoxic stressors via human tau overexpression in N2a cells and in PS19 transgenic mice (Ginsberg et al, 2021;Inda et al, 2020). As noted by Inda and coworkers (Inda et al, 2020), although the identity of individual synaptic plasticity-related proteins impacted by epichaperome formation often differed between stressor conditions, epichaperome-mediated changes in the interaction of these proteins all had functional output imbalances in protein pathways integral for synaptic plasticity.…”

“…Linking epichaperome formation to dysfunction in synaptic plasticity induced by a variety of stressors is highly relevant translationally as it provides a final common path for therapeutically rectifying synaptic plasticity defects (Ginsberg et al, 2021;Inda et al, 2020).…”