Linking Protein Damage in Nerve Cells to Parkinson's and Alzheimer's Diseases

New evidence links oxidative damage in a protein found in nerve cells to the development of degenerative diseases of the nervous system, such as Parkinson's and Alzheimer's.

The first study to provide this evidence, conducted by Penn researchers, was published November 3 in Science magazine.

"The protein, called alpha-synuclein, is one of the building blocks of the brain lesions characteristic in patients with neurodegenerative diseases," said Dr. Virginia Lee, the John H. Ware III Professor in Alzheimer Research and co-director of the Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine at the School of Medicine.

Oxidative damage, she explained, normally occurs when the body's cells are overwhelmed by molecules that have changed because they have combined with nitrogen (nitration) or oxygen (oxidation).

Both types of oxidants damage lipids, nucleic acids, proteins, and other cellular components-much like oxidation causes rust damage to metal in cars and buildings. This damage has been implicated in causing neurodegenerative disorders.

"We found that alpha-synuclein itself is a target of oxidative stress, specifically nitration, within these lesions," said Dr. Lee. "This is the first time anybody has identified nitration on a specific protein."

Neurodegenerative diseases--including Parkinson's, Alzheimer's, diffuse Lewy body disease, and multiple system atrophy--are collectively called synucleinopathies. Most commonly they become symptomatic due to a deficiency of a specific neurotransmitter-in the case of Parkinson's it is dopamine. When the neurons that produce these chemicals die or become impaired, which occurs with oxidation, the eventual results are tremors and sometimes dementia.

"Alpha-synuclein is found at the synapses of nerve cells," explained Dr. Lee. Earlier studies showed that two mutations in the alpha-synuclein gene cause familial Parkinson's disease, and that this protein is also a major component of Lewy bodies, the characteristic lesion in Parkinson's disease.

Penn scientists conducted a series of biochemical tests to determine whether nitrated alpha-synucleins are present, how abundant they are in Lewy bodies, and where they could be found, as well as in what form.

In determining whether the alpha-synucleins found in Lewy bodies are specifically nitrated, Dr. Lee said she and her colleagues found that, "in fact, nitrated alpha-synuclein is a widespread and abundant component of Lewy bodies. It is also an integral component of the filaments that form these lesions and are found in the affected brain regions of synucleinopathies."

Dr. Lee adds: "This is a major foothold in beginning to understand how oxidative stress plays a role in causing Parkinson's and other synucleinopathies." Further studies can help determine the extent of this nitration and find other possible nitrating agents.

"Our studies provide conclusive evidence of oxidative damage in alpha-synuclein, and that such stress may be a primary event leading to the onset and progression of neurodegenerative synucleinopathies, particularly Parkinson's," said Dr. Lee. "This may pave the way for developing therapies to stop or slow the oxidative damage, and thus slow or reverse the progression of these diseases."

In the United States, Parkinson's disease affects over a million people, and Alzheimer's disease about 4 million people.

The research was funded by the National Institute on Aging, the Alzheimer's Association, and the Oxford Foundation.

Almanac, Vol. 47, No. 11, November 7, 2000

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