Receptor May Help Spread of Alzheimer’s and Parkinson’s in Brain

The research identifies a specific type of receptor and suggests that blocking it may help treat of these disorders. The receptors are called heparan sulfate proteoglycans (HSPGs). “Many of the enzymes that create HSPGs or otherwise help them function are good targets for drug treatments,” said senior author Marc I. Diamond, MD, a professor of neurology at the Washington University School of Medicine in St. Louis (MO, USA). “We ultimately should be able to hit these enzymes with drugs and potentially disrupt several neurodegenerative conditions.”

The study’s findings were published online August 2013 in the Proceedings of the National Academy of Sciences of the United States of America (PNAS). Over the 10 years, Dr. Diamond has gathered evidence that Alzheimer’s disease and other neurodegenerative disorders spread through the brain in a manner similar to conditions such as mad cow disease, which are caused by misfolded proteins known as prions.

Dr. Diamond and his colleagues have shown that a part of nerve cells’ inner structure known as tau protein can misfold into a formation called an amyloid. These corrupted versions of tau adhere to each other in clumps within the cells. Similar to prions, the clumps spread from one cell to another, seeding additional dispersal by causing copies of tau protein in the new cell to change into amyloids.

In the new study, first author Brandon Holmes, an MD/PhD student, demonstrated that HSPGs are necessary for binding, internalizing, and dispersing clumps of tau. When he genetically inactivated or chemically modified the HSPGs in cell cultures and in a mouse model, clumps of tau could not enter cells, thereby suppressing the spread of misfolded tau from cell to cell. Mr. Holmes also found that HSPGs are essential for the cell-to-cell spread of degraded forms of alpha-synuclein, a protein linked to Parkinson’s disease.

“This suggests that it may one day be possible to unify our understanding and treatment of two or more broad classes of neurodegenerative disease,” Dr. Diamond concluded. “We’re now sorting through about 15 genes to determine which are the most essential for HSPGs’ interaction with tau,” Mr. Holmes said. “That will tell us which proteins to target with new drug treatments.”

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Washington University School of Medicine in St. Louis