Proteostasis network deregulation signatures as biomarkers for pharmacological disease intervention

Protein homeostasis, or proteostasis, is fundamental to cellular and organismal health. Proteostasis collapse is linked to diverse diseases, including neurodegeneration and cancers. The proteostasis network (PN) comprises the intricately regulated interplay of signaling processes and molecular machines involved in the synthesis, folding, and clearance of the diverse spectrum of proteins comprising the folded, native proteome. Human disease biomarkers are important tools for early detection, individualized phenotyping, and patient stratification and for companion diagnostic use during therapy. With the increasing knowledge and understanding of PN disease alterations, various strategies, such as the modulation of chaperone levels or interference with proteasomal activity, for the therapeutic adjustment of proteostasis deregulation have been devised. To complement the tool kit of therapeutic strategies through chemical chaperones or proteostasis regulator drugs, context-specific biomarkers of PN deregulation will provide important guidance for precise pharmacological proteostasis regulation. Here, we summarize representative studies contributing to our understanding of proteostasis deregulation in age-onset neurodegeneration and cancers, with a focus on the chaperome. We call for a systematic mapping and assessment of the global PN interactome network as a resource for the elucidation of diagnostic and prognostic proteostasis biomarkers.