A computer analysis by two University of Michigan (U-M) researchers shows promise for helping develop therapies for some major diseases by rescuing proteins that have stopped performing normally.
Understanding the role of protein molecules is vital for health research and finding cures and medicines for diseases.
“There are many diseases, including cystic fibrosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, and diabetes, that are products of improperly folded—but potentially functional—proteins,” says lead author Santiago Schnell, Ph.D. (pictured), associate professor of molecular and integrative physiology at the U-M Medical School, and Brehm investigator at the Brehm Center for Diabetes Research. “These diseases are known as protein folding or conformational diseases.”
Conformational diseases can occur when proteins fail to fold into their correct functional states. A folded protein is a complex and useful three-dimensional protein with specific functions.
However, a common hallmark of many conformational diseases is that an otherwise functional protein changes into a misfolded protein that has a higher tendency to aggregate and become harmful to cells and the patient.
The human body has about a million different protein molecules, which serve to manipulate and accommodate important cellular procedures, such as metabolism, signaling cell structures, hormone action, and cell-to-cell interactions. Many common diseases may be treated or cured by designing drugs that can activate or inhibit corresponding protein molecules.
“Our model proposes a couple of remedies for recovering a patient’s own misfolded proteins so they become correctly folded and functional proteins again,” adds Schnell.
“The first remedy is giving the patient a higher concentration of correctly folded proteins to increase the ratio of folded over misfolded proteins. An improved ratio will prevent attack by misfolded proteins. The second remedy is administering drugs to patients to help the proteins fold correctly and to accelerate the folding of proteins, which reduces the chances of misfolding during protein synthesis.”
The authors developed a theoretical model that explains a sudden shift in the concentration of misfolded proteins from a low to a high misfolded concentration inside cells. At high concentration, misfolded proteins become harmful to cells and the patients.
“If we can understand the mechanisms driving toxic misfolded protein production, this will help with the development of medical therapies to reduce misfolded protein production and recover folded proteins that are important to disease prevention,” says co-author Conner I. Sandefur, Ph.D. candidate, U-M Center for Computational Medicine & Bioinformatics.
“This is a really interesting piece of work that has shed light on two critical variables that can influence the toxicity – and ultimately the clinical severity – of protein misfolding diseases like the one we study: misfolded proinsulin that triggers diabetes,” says Peter Arvan, M.D., Ph.D., chief of the Division of Metabolism, Endocrinology & Diabetes, and director of the Comprehensive Diabetes Center.
“These ideas provide compelling directions for us to pursue new therapeutic options to escape the devastating consequences of a variety of protein misfolding diseases,” adds Arvan.
Illustration: University of Michigan.
University of Michigan News Release (04/27/11)
Abstract (Biophysical Journal; Vol. 108, No. 8, 1864-1873 (04/20/11))