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CUMC Town Hall Meeting
To accommodate the schedules of faculty, staff and students, the fall Town Hall meeting led by Dr. Gerald Fischbach will be held on Monday, Oct. 4, at 4 p.m. and repeated on Wednesday, Oct. 6, at 7 a.m. in the P&S Alumni Auditorium.

PARKINSON'S DISEASE

Researchers Pinpoint Possible Cause of Familial Forms of Parkinson's
Problem tracked to protein degradation flaw

David Sulzer
Columbia University Medical Center and Albert Einstein College of Medicine researchers have found that a blockage at protein disposal sites within dopamine neurons may cause some cases of inherited Parkinson's disease. Neurons that release dopamine, the neurotransmitter that controls coordinated movement, slowly die in people with Parkinson's disease, leading to progressively limited mobility and speech.

"The discovery may also indicate the cause of Parkinson's in people with more common forms of the disease and lead to new, more effective treatments to slow or stop the disease progression," says David Sulzer, Ph.D., associate professor of neurology and psychiatry.

Although the majority of Parkinson's cases have no known cause, a few cases are inherited and can be traced to mutations in four different genes, including the gene for the alpha-synuclein protein.

It's unclear why mutant alpha-synuclein causes Parkinson's, but because it accumulates in protein deposits called Lewy bodies found within the dopamine neurons of patients, researchers believe a problem with alpha-synuclein degradation is critical. Learning how mutant alpha-synuclein causes Parkinson's disease may also give tantalizing clues to the cause of more common nonhereditary cases, since neurons in many of these patients are also filled with Lewy bodies rich in alpha-synuclein.

The new research, published in the Aug. 27 issue of Science, suggests that mutant alpha-synuclein causes Parkinson's by binding to a transporter on an important protein disposal site, known as a lysosome, inside the dopamine neurons. The binding then blocks many other types of proteins from entering the lysosome. As a consequence, toxic proteins build up inside neurons, leading eventually to neuronal death. The study was conducted in dopamine neurons taken from mice.

"It's like a garbage truck stalling at the entrance to the town dump," Dr. Sulzer says. "If the truck breaks down right in front of the dump, not only does it fail to deliver its own garbage to the dump, it also blocks all the other garbage trucks and the town fills up with garbage.

"It's a very surprising conclusion. The idea that there's a problem in degradation is not new, but most people have been looking at other degradative pathways," Dr. Sulzer says.

Now Dr. Sulzer and Ana Maria Cuervo, M.D., Ph.D., assistant professor of anatomy and structural biology at Albert Einstein School of Medicine and the study's lead author, are studying whether the same lysosome blockage plays a role in the most common form of Parkinson's, known as "idiopathic." These patients do not carry a mutant alpha-synuclein gene, but their alpha-synuclein proteins bear modifications that may cause the protein to act in the same way as the mutant.

The research was supported by the National Institutes of Health, a National Institute of Neurological Disorders and Stroke Udall Center Grant, the Parkinson's Disease Foundation, the Lowenstein Foundation, the Matheson Foundation, the Huntington's Disease Society of America and the Howard Hughes Medical Institute.

Leonidas Stefanis, M.D., Ph.D., assistant professor of neurology at Columbia University Medical Center, and Harvard researchers Ross Fredenburg and Peter T. Lansbury also participated in the research.

—Susan Conova

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