The protein clumping is part of a "vicious cycle," the researchers said. As the proteins cluster, they inhibit an enzyme that normally breaks them down, leading to the formation of even more masses.
"It's a disease involving accumulation of a protein in an aberrant form," said Dr. Philip Thomas, professor of physiology at UT Southwestern and senior author of the study. The research, available online, was published in the June 17 issue of The Journal of Biological Chemistry.
The findings have parallels to other diseases in which protein clusters form in and around nerves, such as Huntington's and Alzheimer's disease.
The culprit in Parkinson's is the protein alpha-synuclein, which normally appears in a long, folded form in cells. It's known to be linked to the disease because mutations in it cause rare, inherited cases of early-onset Parkinson's.
Normally, if a cell becomes stressed, alpha-synuclein unfolds, and an enzyme degrades it completely into harmless bits to prevent the clumping. In Parkinson's patients, however, some of the degrading enzyme malfunctions and creates truncated fragments of alpha-synuclein rather than the harmless bits.
UT Southwestern researchers found that these truncated fragments act like "seeds," encouraging the unfolded form of alpha-synuclein to gather around them. It doesn't take much just a few molecules of the truncated fragments to activate this process. Eventually, the cluster is big enough to form a structure called a fibril.
The two forms of the enzyme are usually in balance, with the normal activity outperforming the malicious activity, Dr. Thomas said.
But when the system goes out of balance, the fibrils suppress the normally functioning enzyme,
Contact: Aline McKenzie
UT Southwestern Medical Center