When Good Proteins Go Bad
Proteins are the building blocks of life. Every cell, tissue and organ in the body is made by and from proteins. Most of the time, they do their jobs with amazing reliability. But what happens when something goes wrong?
Genes may get the glory, but in the day-to-day life of cells, it’s proteins that do most of the work. While genes remain safe and sheltered inside the cell’s nucleus, proteins are out there on the front lines doing everything it takes to keep cells alive, healthy and functioning normally.
There’s a lot of turnover in the protein business. Human cells must synthesize thousands of new proteins every minute to replace old ones that wear out and are recycled back into their component parts.
The first step in protein synthesis takes place in a part of the cell called the ribosome. Following genetic instructions, the ribosome selects specific amino acids from a pool of 20 possible variations and strings them together to make a long chain. Then, this chain of amino acids is folded into one specific three-dimensional shape.
For many proteins, folding takes place inside a cellular compartment called the endoplasmic reticulum. Other proteins are produced and folded at different locations within the cell. No matter where it takes place, the details of exactly how this feat of cellular origami occurs are still unclear. And, as with any complex process, there are lots of things that can go wrong along the way.
Proteins can be fussy. If they get too hot, they fall apart. If it’s too acidic, they stop working. They require helper molecules called chaperones to push and pull them into the correct shape. If their chaperone-of-choice isn’t available, they won’t fold.
A cell has several ways of dealing with a protein-folding problem. It can shut down protein production, giving it time to catch up with a folding backlog. It can make more chaperones to guide proteins through the folding process. It can digest unfolded proteins and recycle the component parts. But one way or another, the cell has to do something quickly because if nothing works, it’s going to die.
Folding errors can result in the absence of a protein that’s required for normal cell function, a misfolded protein that cannot do its job, or — most dangerous of all — a clump of sticky abnormal protein called amyloid. Regardless of the type of protein abnormality, the effect on the cell can be catastrophic. Improperly folded proteins are never a good thing, and aggregations of misfolded protein can be toxic.
“Protein folding is the most error-prone step in gene translation,” says Randal Kaufman, Ph.D., the Warner-Lambert/Parke-Davis Professor of Medicine who has studied protein folding since the 1980s. “The more difficult the protein is to fold, the greater the association with disease.”
Researchers are just beginning to understand the connections between abnormal protein folding and human disease. The growing list of what are now called protein misfolding diseases includes Alzheimer’s disease and other dementias, atherosclerosis, cancer, congenital hypothyroidism, cystic fibrosis, diabetes, fatty liver disease, hemophilia, polycystic kidney disease, Parkinson’s disease and retinitis pigmentosa.
Protein folding is an area of strong research focus at the U-M. Teams of scientists and clinicians from many disciplines are working together to study the effects of abnormal protein folding in different types of cells and different diseases. But sorting out all the factors involved is not easy.
It’s one thing to study protein folding in a test tube, but determining exactly how folding defects contribute to disease in a cell or a living organism is far more difficult, according to Kaufman. “It’s like looking at an automobile crash and trying to figure out what went wrong,” he says.
Death by Toxic Protein
Unlike many cells, neurons in the brain are not expendable. If you kill a muscle cell, the body just grows a new one. If you kill a neuron, it is not easily replaced and any memory stored in that neuron is gone forever. This makes the brain particularly vulnerable to the lethal effects of toxic proteins.
There are many types of neurodegenerative disease, each characterized by toxic deposits of a different abnormal protein in the brain. People with Alzheimer’s disease have accumulations of two different proteins — beta-amyloid outside neurons, and tau inside — the so-called plaques and tangles of Alzheimer’s. In Parkinson’s disease, a protein called alpha-synuclein forms aggregates called Lewy bodies. Huntington’s disease and eight other hereditary polyglutamine disorders each involve a different abnormal protein.
Regardless of the specific protein involved, the outcome is the same. Slowly and inexorably, neurons die and the brain is destroyed. It’s unclear whether deposits of toxic protein actually cause the disease or are just byproducts of the disease process. There is still no definite answer to one basic question: What kills the neurons?