Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv 69978, Israel.
J Biol Chem. 2013 Jun 14;288(24):17579-88. doi: 10.1074/jbc.M112.434787. Epub 2013 May 1.
The development of disease-modifying therapy for Parkinson disease has been a main drug development challenge, including the need to deliver the therapeutic agents to the brain. Here, we examined the ability of mannitol to interfere with the aggregation process of α-synuclein in vitro and in vivo in addition to its blood-brain barrier-disrupting properties. Using in vitro studies, we demonstrated the effect of mannitol on α-synuclein aggregation. Although low concentration of mannitol inhibited the formation of fibrils, high concentration significantly decreased the formation of tetramers and high molecular weight oligomers and shifted the secondary structure of α-synuclein from α-helical to a different structure, suggesting alternative potential pathways for aggregation. When administered to a Parkinson Drosophila model, mannitol dramatically corrected its behavioral defects and reduced the amount of α-synuclein aggregates in the brains of treated flies. In the mThy1-human α-synuclein transgenic mouse model, a decrease in α-synuclein accumulation was detected in several brain regions following treatment, suggesting that mannitol promotes α-synuclein clearance in the cell bodies. It appears that mannitol has a general neuroprotective effect in the transgenic treated mice, which includes the dopaminergic system. We therefore suggest mannitol as a basis for a dual mechanism therapeutic agent for the treatment of Parkinson disease.
治疗帕金森病的疾病修饰疗法的发展一直是药物开发的主要挑战之一，包括需要将治疗剂递送到大脑。在这里，我们研究了甘露醇除了破坏血脑屏障的特性外，还能在体外和体内干扰α-突触核蛋白聚集过程的能力。通过体外研究，我们证明了甘露醇对α-突触核蛋白聚集的影响。虽然低浓度的甘露醇抑制原纤维的形成，但高浓度显著减少四聚体和高分子量寡聚物的形成，并将α-突触核蛋白的二级结构从α-螺旋转变为不同的结构，表明聚集的替代潜在途径。当给予帕金森果蝇模型时，甘露醇显著纠正了其行为缺陷，并减少了治疗果蝇脑中的α-突触核蛋白聚集体的数量。在 mThy1-人α-突触核蛋白转基因小鼠模型中，治疗后几个脑区的α-突触核蛋白积累减少，表明甘露醇促进细胞体中α-突触核蛋白的清除。甘露醇似乎对转基因治疗小鼠具有普遍的神经保护作用，包括多巴胺能系统。因此，我们建议甘露醇作为治疗帕金森病的双重机制治疗剂的基础。
