SLU Scientists Identify Chemical that Triggers Parkinson’s Disease

New Research Could Yield Therapies to Slow or Stop the Disorder
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ST. LOUIS - Researchers at the Saint Louis University School of Medicine have discovered the key brain chemical that causes Parkinson's disease - a breakthrough finding that could pave the way for new, far more effective therapies to treat one of the most common and debilitating neurological disorders.

Currently, the main approach for treating Parkinson's disease, which afflicts more than 1.5 million Americans, is to replace dopamine that's lost when the cells that produce it die off and cause the disorder. With this new research, however, scientists can better work toward 'neuroprotective' therapies - those that actually block dopamine cells from dying off in the first place.

"We believe this work represents a very significant breakthrough in understanding the complicated chemical process that results in Parkinson's disease," said William J. Burke, M.D., Ph.D., professor of neurology at the Saint Louis University School of Medicine and the study's lead author.

"For the first time, we've identified the chemical that triggers the events in the brain that cause this disorder," Burke added. "We believe these findings can be used to develop therapies that can actually stop or slow this process."

The scientists' findings are published in an early online edition of the journal Acta Neuropathologica (http://www.springerlink.com/content/.../fulltext.html).

Parkinson's disease occurs when some nerve cells in a part of the brain called the substantia nigra die or become impaired. Normally, these cells produce dopamine - a vital chemical that allows smooth, coordinated function of the body's muscles and movements.

When about 80 percent of these dopamine-producing cells die or are damaged, the symptoms of Parkinson's disease begin to appear. These include tremors and shaking, slowness of movement, rigidity and stiffness, and difficulty with balance.

Scientists have long known that a key protein called alpha-synuclein plays a role in the development of Parkinson's disease. Alpha-synuclein is found throughout the brain - but in some people, the protein clumps together. This causes the death of the dopamine-producing cells, which in turn causes Parkinson's to develop.

The SLU researchers discovered that dopamine itself actually plays a role in destroying the cells that produce it.

In the process that leads to Parkinson's disease, dopamine is converted into a highly toxic chemical called DOPAL. Using test-tube, cell-culture and animal models, the researchers found that it is DOPAL that causes alpha-synuclein protein in the brain to clump together, which in turn triggers the death of dopamine-producing cells and leads to Parkinson's.

"This is very exciting," Burke said. "This is the first time that anyone has ever established that it is a naturally occurring byproduct of dopamine that causes alpha-synuclein to aggregate, or clump together. It's actually DOPAL that kicks this whole process off and results in Parkinson's disease."

The research was supported by grants from the Missouri ADRDA Program, the Nestle Foundation, the St. Louis Veterans Administration Medical Center, the National Institutes of Health, the American Federation on Aging Research, the Alan A. and Edith L. Wolff Charitable Trust and the Blue Gator Foundation.

Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious disease.

Authors
Carsten R. Bjarkam, Jens Chr. Sørensen, Niels Å. Sunde, Finn A. Geneser, Karen Østergaard
1University of Aarhus
2University Hospital of Aarhus
3University Hospital of Aarhus


Abstract

Neurodegenerative diseases are often considered incurable with no efficient therapies to modifyor halt the progress of disease, and ultimately lead to reduced quality of life and to death.Our knowledge of the nervous system in healthand disease has, however, increased considerably during the last fifty years andtoday, neuroscience reveals promising newstrategies to deal with disorders of thenervous system.Some of these results have been implementedwith success in the treatment of Parkinson'sdisease, a common neurodegenerative illnessaffecting approximately 1% of the populationaged seventy or more. Parkinson's disease ischaracterized by a massive loss of dopaminergicneurons in the substantia nigra, leading tosevere functional disturbance of the neuronalcircuitry in the basal ganglia. A thoroughdescription of basal ganglia circuitry inhealth and disease is presented. We describehow the functional disturbances seen inParkinson's disease may be corrected atspecific sites in this circuitry by medicaltreatment or, in advanced stages of Parkinson'sdisease, by neurosurgical methods. The latterinclude lesional surgery, neuraltransplantation and deep brain stimulation,together with future treatment strategies usingdirect or indirect implantation of geneticallymodified cell-lines capable of secretingneurotrophic factors or neurotransmitters.Advantages and disadvantages are brieflymentioned for each strategy and theimplications for the future and the possibleuse of these interventions in otherneurodegenerative diseases are discussed, withspecial emphasis on deep brain stimulation.

Keywords
basal ganglia, basal ganglia circuitry, deep brain stimulation, immortalized cell-lines, neural stem cells, neural transplantation, neurotrophic factors

"In the process that leads to Parkinson's disease, dopamine is converted into a highly toxic chemical called DOPAL. "
I have always wondered if PD is caused by the excessive need and use of dopamine ... a stress caused by over-use?
I also wonder if this article gives weight to the theory that while L-dopa drugs relieve symptoms temporarily, they also accelerate the disease????