Type 2 diabetes may be the result of protein folding gone awry. Changes in structure, not chemistry, cause problems. Illnesses from Alzheimer’s disease, Type II diabetes and Creutzfeldt-Jakob disease may be the result of protein folding gone awry.
Two new studies in the journal Nature report that misfolded proteins that clump together are harmful because of their abnormal shape, not because their chemistry has become toxic.
The findings suggest future therapies designed to prevent or target the misfolded proteins may help treat seemingly unrelated diseases. Christopher M. Dobson, a professor of chemistry and structural biology at the University of Cambridge in England, was a co-investigator on the first study.
Proteins need to collapse into one another to determine what their ultimate function will be.
For the last decade, Dobson’s research has focused on how proteins go from their disordered state after they are first made inside a cell into their folded, functional state.
"As we were very much involved in understanding the folding process, we were able to focus on a different angle, which is what makes the protein misfold," he says.
Dobson says the deposits that form in the 20 or so protein misfolding conditions — including Alzheimer’s disease, the prion diseases (such as Creutzfeldt-Jakob disease), and even Type II diabetes — are made up of thread-like structures.
However, he found that aside from the proteins linked to those diseases, other proteins in the laboratory could be "persuaded" to take these thread-like forms.
"We could form these thread-like structures in the test tube from virtually any protein that we wanted to if we got it under the right conditions," Dobson says. Moreover, "if you take any protein and misfold it into these aggregates [an abnormal collection of proteins], they will be damaging to the cells."
He explains this misfolding appears to happen when the normal process of protein folding goes awry, and the protein bonds incorrectly to itself. Dobson suspects that when this happens, "sticky" parts of the early aggregate protein that are normally hidden inside the properly folded protein are exposed, interfering with other parts of the cell.
As the more mature protein threads form, says Dobson, "a lot of the sticky regions of the protein get covered up and you end up with a rather innocuous type of material."
Other proteins called "molecular chaperones" normally protect folding proteins and destroy those that have misfolded. Dobson suspects that since most of the misfolding-related diseases are linked to aging, perhaps these cellular housekeeping functions become less efficient with time.
"We tend to accumulate these aggregates under some circumstances," he says. "Once these aggregates start to form, they actually seed the formation of other aggregates, and one can end up with large quantities of them."
He says that understanding the fundamental structural mechanisms of this misfolding may lead to new therapies for illnesses like Alzheimer’s disease. In particular, he says, "if one wants an effective therapy, one should either try and stop the aggregates forming at all … or else try and get rid of these early aggregates."
"This is an entirely new way of thinking about what causes a whole variety of diseases of old age," Walker says. "The good news is that people are thinking in this way, and this is going to lead to — more or less — a revolution in the way we think about these [proteins] and a revolution in the way we think about treating the diseases."
Walker says that scientists are now on the threshold of new discoveries. "Hopefully … we’ll be able to use what we learn to treat a variety of diseases that have always been thought of as being completely unrelated."