Isoprenoids, neuromelanin and neuronal vulnerability in Parkinson's disease

帕金森氏症是一种常见的、最终致命的脑部疾病，主要影响正常的运动。虽然帕金森氏症患者大脑其他区域的细胞死亡相对较少，但运动症状是由特定脑细胞的大量死亡引起的，这些脑细胞的独特之处在于它们含有一种名为神经黑色素的色素。该项目旨在发现是什么使大脑中含有神经黑色素的细胞在帕金森病中特别容易受到细胞死亡的影响。我们最近发现，帕金森氏病患者细胞中的神经黑色素浓缩了一种名为α-突触核蛋白的脂肪结合蛋白，这种蛋白被认为是导致帕金森氏症细胞死亡的重要原因。神经黑色素和α-突触核蛋白之间的这种联系在帕金森氏症大脑中不含色素的其他细胞中没有发现，在健康人的大脑中也没有发现。我们还发现，三分之一的神经黑色素是由一组特殊的脂肪组成的，这种脂肪被称为类异戊二烯。这些脂肪的变化已经在帕金森氏症患者的血液中得到报道。我们认为，帕金森病患者神经黑色素中类异戊二烯脂肪的特定变化会导致α-突触核蛋白在色素中的脂肪上积累，以及其他对细胞有害的细胞变化，最终导致细胞死亡。这些变化可能首次解释了为什么含有神经黑色素的脑细胞在帕金森氏症中特别脆弱，并为治疗这种疾病提供了新的途径。

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.