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Protein Misfolding: Origami Medicine

The proteostasis network has always existed, but the name is new, and only recently emerging is the notion that the network is as essential to life as a beating heart or DNA. Proteostasis is what the cell aspires to: a state of equilibrium in which the many proteins inside it coexist and interact. When the network is perfectly balanced, it’s a hallmark of a healthy cell—and of any healthy organism, from the primitive worm Caenorhabditis elegans to the gloriously complex human. But when it’s unbalanced—because of defective proteins, aging, physiological stress or other factors—disease results.

Despite its name, proteostasis is anything but static. There’s constant activity, as every day the cells of the human body pump out thousands of proteins that carry out a remarkable range of functions, from preventing lung tissue damage to transporting crucial ions across membranes and stabilizing nerve cells. To achieve these functions, proteins must fold into specific three-dimensional shapes, find their way to their destinations and, if defective or no longer needed, degrade to make way for newly synthesized replacements. A network of more than 1,000 enzymes, molecular chaperones and other components controls these processes. Numerous signaling molecules work together in pathways that respond to cues from the cell or its environment to regulate the number of chaperones, enzymes and components.

William Balch, professor of cell biology at the Scripps Research Institute in La Jolla, Calif., whose work focuses on the pathways of proteostasis, describes the process of folding, transporting and chaperoning a protein: “It’s like raising a kid. After he’s born, you don’t just put him out on the street. You work with him. The cell is working all the time with the proteins that it makes on a minute-by-minute basis.” Each cell must ensure that proteins are made to proper specifications, maintained in the three-dimensional shape that allows them to work properly, and launched into adulthood in a way that supports the cell’s overall health.

Though many scientists are now focused on deciphering the details of the system, progress has been frustratingly slow, and the more researchers learn, the more complexities they unearth. Discovering the processes and interactions involved in just one pathway may take years. But there’s an urgency underlying this work, because folding errors and other protein defects are known or suspected to be implicated in many devastating diseases, from cystic fibrosis to Huntington’s, Alzheimer’s and type 2 diabetes.

One tack medical science has taken is to try to treat these disorders with gene therapy—replace the defective gene that produces the aberrant protein. Researchers have also looked for ways to introduce a “normal,” or “wild type,” version of the protein into a cell. For example, with a degenerative nerve disease known as transthyretin (TTR) amyloid polyneuropathy, caused by a misfolded protein produced by the liver, a transplanted liver cures the condition by making perfect, wild-type TTR that doesn’t cause problems. But in most cases, these methods haven’t proved effective, so the treatment of misfolding disorders has usually been relegated to relieving symptoms.

Recently, however, researchers have begun exploring ways that science can influence parts of the process, tweaking the diseased system with drugs designed to bring proteostasis back into balance. In some cases, they’ve been able to make partial molecular fixes that help a misfolded protein achieve its original purpose. Sometimes, it turns out, perfection isn’t needed, and “good enough” solutions, hurried from concept to drug discovery through a process of high-technology trial and error, may get the job done—often years in advance of more complete or elegant therapies.