'Vicious cycle' of protein formation involved in Parkinson's disease
DALLAS ? June 21, 2005 ? Researchers at UT Southwestern Medical Center have
discovered a mechanism that causes a protein to clump together in brain
cells of people with Parkinson's disease, pointing toward a possible
treatment for the condition.
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, preventing it from fully breaking down the unfolded
alpha-synuclein, resulting in even more of the protein being available to
form clumps. The clumps also alter the structure of the enzyme in such a
way that it produces even more seed fragments. This leads to the formation
of more clumps, and so on.
Scientists are still debating which form of the alpha-synuclein protein
actually damages the cells, said Dr. Chang-Wei Liu, research fellow in
physiology at UT Southwestern and lead author of the study. It could be the
mature fibril, or one of the intermediate forms that appears during the
degradation process, he said.
Future research may involve uncovering methods to inhibit just the
malicious form of the enzyme, while leaving the functions of the normal
enzyme unaffected, Dr. Thomas said. Inhibiting only one form is vital,
because the normal enzyme is necessary for cells to survive.
Still, the finding reported in The Journal of Biological Chemistry "gives
us clues about potential new treatment avenues," he said.
Other UT Southwestern authors of the study are Karen Lewis, student
research assistant in physiology, and Dr. George DeMartino, professor of
physiology. Researchers at the University of Pennsylvania School of
Medicine also contributed.
###
The work was funded by the National Institutes of Health and the
Parkinson's Disease Foundation.
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