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PDF Interprets: Three Factors Contribute to Cell Death

Scientists at Columbia University, led by Eugene V. Mosharov, Ph.D., and David Sulzer, Ph.D., have confirmed a long-standing hypothesis that too much dopamine within certain brain cells leads to the cell death that causes Parkinson’s.  However, whether neurons die also depends on calcium levels and the presence of the protein alpha-synuclein. The study appeared in the April 30 edition of the journal Neuron

This study tries to understand why dopamine neurons die in Parkinson's disease - a hallmark sign of the disease that leads to its motor symptoms.

In people with Parkinson’s, the dopamine-producing brain cells in a region called the substantia nigra are unusual in several ways.  They have elevated levels of dopamine floating free within the cells, as well as higher than normal calcium levels.  They also accumulate the protein alpha-synuclein. 

To better understand how each of these factors contributes to cell death, the researchers used a cutting-edge technique they developed called intracellular patch electrochemistry to directly measure the amount of dopamine within dopamine neurons grown in culture. 

As they predicted, elevated levels of the so-called cytosolic dopamine were toxic to neurons.  Decreasing these levels, either genetically or with pharmaceuticals, successfully prevented cell death.  However, even with high dopamine levels, decreasing the level of calcium in the cells also made them more likely to live.  And cells that lacked alpha-synuclein were more resilient against elevated dopamine than those that contained the protein.

The researchers conclude that it takes a combination of factors — "multiple hits" — to make dopamine neurons vulnerable.  They believe that therapies interfering with any one of them could protect cells.

Lead researchers Eugene V. Mosharov, Ph.D., and David Sulzer, Ph.D. are both supported through PDF’s annual Center Grant to Columbia University.

 

Source Date: May 18 2009