WHAT IT IS
Chaperones are proteins that are best known as regulators of protein folding. Chaperones help new proteins fold correctly, help refold misfolded proteins, and regulate disposal of proteins that cannot be refolded. Collectively, chaperones, co-chaperones, and other factors make up the so-called chaperome, which is responsible for protein homeostasis in the cell.
Two chaperones, heat shock proteins 70 (HSP70) and 90 (HSP90) play especially critical roles in protein homeostasis, since they act as the core of short-lived multi-protein scaffolds that carry out much of the folding and refolding work of the chaperome.
Work by Gabriela Chiosis, PhD, of the chemical biology program at Memorial Sloan Kettering Cancer Center in New York City, has revealed that in many types of cancer cells, these normally short-lived scaffolds become stabilized, a condition she has termed the epichaperome, to stress that, akin to epigenetic (post-translational) changes in other proteins, the change is not in the level of expression of the individual chaperones, but in the structure and behavior of the complex.
HOW IT WORKS
Because the chaperome is composed of over 200 dynamically interacting proteins, much remains to be learned about the detailed function of the chaperome in cellular health and disease. Research by Dr. Chiosis suggests that prolonged cellular stress is a trigger for stabilization of chaperone platforms—that is, creation of an epichaperome complex. The epichaperome then affects a variety of cellular pathways, depending on the cell, the type of stress, and other context-dependent factors. Neurons are among the most sensitive cell types to disruptions of internal processes, and Dr. Chiosis's research suggests that epichaperome-mediated dysfunction can affect pathways that contribute to development of Alzheimer's disease.
HOW IT IS APPLIED
Because misfolded amyloid-beta and tau are the central pathology of Alzheimer's disease, attempts have been made to manipulate individual chaperones for therapy in the disease, including through upregulating and downregulating their activity or expression. To date, these attempts have not led to clinical success. An epichaperome inhibitor is currently undergoing early clinical trials in three types of cancer. Identification of the role of the epichaperome in AD models has led to development and early clinical testing of an inhibitor of epichaperome stabilization in that disease as well.