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Study Identifies Possible Trigger for Parkinson's Disease


For release: Monday, February 25, 2008

A chemical interaction that blocks cells' ability to break down damaged proteins may trigger development of Parkinson's disease (PD), a new study shows.   Finding ways to overcome the blockage could lead to strategies for preventing the disease or stopping its progression.

A reaction between the nerve-signaling chemical dopamine and a protein called alpha-synuclein leads to the problem.  Dopamine changes alpha-synuclein in a way that causes it to get stuck in the membranes surrounding the cells' recycling centers – enzyme-filled structures called lysosomes.  This results in a cellular "traffic jam" that prevents alpha-synuclein and other molecules from entering the lysosomes and being broken down.  As a result, neurons become more vulnerable to stress.  This may cause the degeneration of dopamine-producing neurons, leading to the tremors and other symptoms of PD.

"We have found that when alpha-synuclein reacts with dopamine, it makes a change in the protein that blocks the cell's recycling system," says Ana Maria Cuervo, M.D., Ph.D., of Albert Einstein College of Medicine in New York, who led the study.  “If there was a way to prevent this blockage, we might be able to delay the onset of symptoms in Parkinson’s disease.” 

Previous studies have shown that mutated alpha-synuclein, found in some people with early-onset PD, blocks the process by which cells detect defective proteins and other molecules and transport them to lysosomes for recycling.  This process is called autophagy.  However, alpha-synuclein mutations are found in only 5-10 percent of people with PD.  The new study explains how PD may develop in people with normal alpha-synuclein genes.  The research was funded in part by National Institute of Neurological Disorders and Stroke Udall Center grants and by the National Institute on Aging.  It appears in the February 2008 issue of The Journal of Clinical Investigation.[1] 

“The novelty of this study is showing that dopamine is a critical component of the problem,” Dr. Cuervo says.  The findings help explain why dopamine-producing neurons are lost in PD while other cells are spared.

In the study, the researchers looked at the effects of several modified forms of alpha-synuclein in cultured cells and in lysosomes isolated from rat liver cells.  They found that most of the modified forms of alpha-synuclein prevented the protein from being recycled as efficiently as the normal form of the protein.  The alpha-synuclein modified by dopamine, however, also blocked the breakdown of other proteins.  The researchers also showed that the blockage triggered cell death in neurons.  The problem occurred only in neurons with high levels of both alpha-synuclein and dopamine. 

“It is an unfortunate property of alpha-synuclein that it interacts with dopamine in this way,” Dr. Cuervo says. 

It is not yet clear why certain people are vulnerable to PD while others are not.  Everyone has alpha-synuclein in dopamine-producing neurons, but only some people lose enough dopamine neurons to develop PD.  The researchers believe neurons may be able to compensate for the blockage caused by alpha-synuclein and dopamine until something else stresses them, Dr. Cuervo says.  She is particularly interested in whether oxidative stress – a side effect of metabolism – may contribute to the development of PD. 

Dr. Cuervo's findings also suggest that treatment with levodopa, a standard treatment for PD that increases the level of dopamine in the brain, may interact with alpha-synuclein to speed the neurodegeneration caused by the disease.  Many previous studies have suggested that levodopa might contribute to the death of dopamine neurons, but results so far have been inconclusive. 

The researchers are now planning studies that will cross-breed animal models of PD with transgenic animals that have reduced susceptibility to age-related decline in autophagy, Dr. Cuervo says.  The results should help to determine what age-related factors affect development of PD.  Researchers also need to look for ways to prevent or overcome the toxic effects of dopamine-modified alpha-synuclein.  It might be possible, for example, to reduce levels of alpha-synuclein in the cells or to increase the lysosomes’ ability to recycle proteins.  With more research, these strategies might eventually lead to improved treatments for PD.

The NINDS is a component of the National Institutes of Health (NIH) within the Department of Health and Human Services.  The NIH — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research. It investigates the causes, treatments, and cures for both common and rare diseases.  For more information about NIH and its programs, visit http://www.nih.gov.

-By Natalie Frazin

[1]Martinez-Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzuli J, Mosharov EV, Hodara R, Fredenburg R, Wu D-C, Follenzi A, Dauer W, Przedborski S, Ischiropoulos H, Lansbury PT, Sulzer D, Cuervo A.M.  "Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy."  The Journal of Clinical Investigation, February 2008, Vol. 118, No. 2, pp. 777-786.

Last Modified February 25, 2008