Maguire-Zeiss Kathleen A
Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road, Washington, DC 20057, United States.
Pharmacol Res. 2008 Nov-Dec;58(5-6):271-80. doi: 10.1016/j.phrs.2008.09.006. Epub 2008 Sep 16.
Parkinson's disease is a progressive age-related neurodegenerative disease with invariant loss of substantia nigra dopamine neurons and striatal projections. This disorder is well known for the associated motoric symptoms including resting tremor and the inability to initiate movement. However, it is now apparent that Parkinson's disease is a multisystem disorder with patients exhibiting symptoms derived from peripheral nervous system and extra-nigral dysfunctions in addition to the prototypical nigrostriatal damage. Although the etiology for sporadic Parkinson's disease is unknown, information gleaned from both familial forms of the disease and animal models places misfolded alpha-synuclein at the forefront. The disease is currently without a cure and most therapies target the motoric symptoms relying on increasing dopamine tone. In this review, the role of alpha-synuclein in disease pathogenesis and as a potential therapeutic target focusing on toxic conformers of this protein is considered. The addition of protofibrillar/oligomer-directed neurotherapeutics to the existing armamentarium may extend the symptom-free stage of Parkinson's disease as well as alleviate pathogenesis.
帕金森病是一种与年龄相关的进行性神经退行性疾病，黑质多巴胺能神经元和纹状体投射会持续丧失。这种疾病以相关的运动症状而闻名，包括静止性震颤和运动启动障碍。然而，现在很明显，帕金森病是一种多系统疾病，除了典型的黑质纹状体损伤外，患者还表现出来自外周神经系统和黑质外功能障碍的症状。尽管散发性帕金森病的病因尚不清楚，但从该疾病的家族形式和动物模型中获得的信息表明，错误折叠的α-突触核蛋白处于首要位置。目前该疾病无法治愈，大多数治疗方法针对运动症状，依靠增加多巴胺水平。在这篇综述中，我们考虑了α-突触核蛋白在疾病发病机制中的作用以及作为一种潜在治疗靶点（聚焦于该蛋白的毒性构象）的情况。在现有治疗手段中增加原纤维/寡聚体导向的神经治疗方法，可能会延长帕金森病的无症状期，并减轻发病机制。
