Kaji Ryuji, Goto Satoshi, Tamiya Gen, Lee L V
Department of Clinical Neuroscience, Tokushima University.
Rinsho Shinkeigaku. 2005 Nov;45(11):811-4.
Pathological findings in dystonia have been unclear. X-linked recessive dystonia-parkinsonism (XDP, DYT3), endemic in the Panay island, the Philippines, is characterized by the clinical onset with dystonia followed by parkinsonism. It provides a unique opportunity to explore the anatomical basis of dystonia, because it has discernible pathological changes even at its early phase of dystonia. After extensive searches for the anatomical basis in XDP, we found selective loss of striosomal neurons in the striatum in dystonic patients' brain. Because striosomal neurons inhibit nigrostriatal dopaminergic neurons via GABAergic innervation, the striosomal lesion could account for dopamine excess in the striatum, which in turn causes a hyperkinetic state or dystonia. We also identified the causative gene as one of the general transcription factor genes, TAF1. This abnormality markedly reduced the expression of dopamine D2 receptor gene (DRD2) in neurons. XDP has certain similarities to Huntington disease not only in pathological and clinical findings, but also the molecular mechanism, which disturbs expression of genes essential for striatal neurons, such as DRD2. Therapeutic intervention may become possible through pharmacological measures that affect gene expression.
肌张力障碍的病理发现一直不明确。X连锁隐性肌张力障碍-帕金森综合征（XDP，DYT3）在菲律宾班乃岛流行，其特征是临床以肌张力障碍起病，随后出现帕金森综合征。它为探索肌张力障碍的解剖学基础提供了独特的机会，因为即使在肌张力障碍的早期阶段也有可辨别的病理变化。在对XDP的解剖学基础进行广泛研究后，我们发现肌张力障碍患者大脑纹状体中纹状小体神经元选择性缺失。由于纹状小体神经元通过GABA能神经支配抑制黑质纹状体多巴胺能神经元，纹状小体病变可解释纹状体中多巴胺过量，进而导致运动亢进状态或肌张力障碍。我们还确定致病基因是一般转录因子基因之一，即TAF1。这种异常显著降低了神经元中多巴胺D2受体基因（DRD2）的表达。XDP不仅在病理和临床发现上，而且在分子机制上与亨廷顿病有某些相似之处，后者会干扰对纹状体神经元至关重要的基因如DRD2的表达。通过影响基因表达的药理学措施可能实现治疗干预。
