Isoprenoids, neuromelanin and neuronal vulnerability in Parkinson's disease

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Parkinson's disease is a common and ultimately fatal brain disease which affects primarily normal movement. While a comparatively modest cell death occurs in other areas of the brain in Parkinson's disease, the motor symptoms result from the massive death of particular brain cells which are unique in that they contain a pigment called neuromelanin. This project aims to discover what makes the neuromelanin-containing cells of the brain particularly vulnerable to cell death in Parkinson's disease. We recently found that neuromelanin pigment in the cells of people who have died with Parkinson's disease concentrate a fat-binding protein called alpha-synuclein which is thought to be important in causing cell death in Parkinson's disease. This association between the neuromelanin pigment and alpha-synuclein was not found in other cells in Parkinson brain which do not contain pigment, nor in the brains of healthy people. We also found that a third of neuromelanin is made up of a special group of fats called isoprenoids. Changes in these fats have already been reported in the blood in Parkinson's disease. We suggest that specific changes in the isoprenoid fats in neuromelanin in Parkinson's disease cause alpha-synuclein protein to accumulate on the fat in the pigment, as well as other cellular changes which are detrimental to the cell, ultimately leading to the death of the cell. These changes may explain for the first time why neuromelanin-containing brain cells are especially vulnerable in Parkinson's disease and provide new avenues for treating this disorder.