Protector of Dopamine Neurons ID'd, New Lead in Parkinson's Fight

Newswise — Scientists reveal a function of a human protein in today's issue of Science Express, and this new understanding could later prove key in preventing Parkinson's disease, according to a University of Alabama professor who co-authored the study.

Properly functioning cells have tiny "postal systems" within, efficiently delivering proteins and other "packages" to other parts of the cell. Deliveries can become blocked leading to serious disorders, but in today's announcement, researchers say they have identified a new cellular "express deliverer" which can accelerate package arrivals.

Identification of this express mail deliverer, a naturally occurring protein known as RAB-1, helps define a new cellular pathway and is a step that may eventually lead to prevention of Parkinson's disease, said Dr. Guy Caldwell, associate professor of biological sciences at The University of Alabama and one of the paper's three UA co-authors. The collaborative effort involves scientists representing about a dozen different universities and research institutes, led by renowned expert in cell biology, Dr. Susan Lindquist of The Whitehead Institute and M.I.T.

"Our cells have what might be thought of as a postal system where they deliver the mail, in the form of proteins or chemicals like dopamine, to different areas of the cell," said Caldwell. "For the delivery to occur properly, it has to be packaged in what we call vesicles within the cell membranes. What this paper shows, for the first time, is that in multiple models for Parkinson's disease, this trafficking, or the process of delivering the mail, is interfered by a protein, alpha-synuclein, which has been found to cause Parkinson's."

Too much alpha-synuclein essentially disrupts this intra cellular delivery system, said Caldwell, the state's current Carnegie Foundation/CASE Professor of the Year. Conversely, the protein RAB-1, which is naturally present in humans and all the animal models used in this research study, has now been shown to accelerate cell trafficking.

"It's a cellular postman, if you will," Caldwell said. "If we add more RAB-1, we essentially have more postmen, and things could get delivered better."

Songsong Cao, a former graduate student in the Caldwell Lab, and Dr. Kim Caldwell, assistant professor of biological sciences, are UA's additional co-authors on the study. When dopamine-producing neurons within the human brain do not receive proteins necessary to manage dopamine levels, this leads to their malfunction or cell death. This, in turn, leads to the hallmark symptoms that the 1 million Americans with Parkinson's know all too well, rigid and tremoring limbs, difficulty in movement and impaired reflexes.

"If dopamine doesn't get 'packaged,'" Caldwell said, continuing with the postal analogy, "it stays in the cytoplasm, where it's more easily oxidized."

Scientists already knew that alpha synuclein played a role in Parkinson's, but this study has led to a better understanding of how it impacts our brain cells, the researchers said.

To function correctly, proteins must fold properly within cells. One misfolding, as can occur when extra copies of the protein alpha-synuclein are present, can lead to others and, subsequently, to aggregation, or clumping, of proteins. Aggregation of proteins can lead to neuron malfunction or cell death.

The next step, Caldwell said, is to identify and develop a molecule, in drug form, that could either mimic the effect the cellular postman, RAB-1, has or one that will enhance RAB-1 production within the body.

The joint research published in Science Express, an advanced electronic publication of select research papers accepted by Science, was performed, and complementary results obtained, in various research models, including yeast, fruit flies, worms and rats. Criteria for the online posting of upcoming Science articles are the timeliness and importance of the research, according to Science Express.

The Caldwell Lab, housed within UA's College of Arts and Sciences, was invited to join this particular research effort six months ago.

"This was a highly collaborative paper," Caldwell said. "I think the best science is done that way."

Supplementary graphics are available here: http://uanews.ua.edu/