[Molecular and anatomical bases of dystonia: X-linked recessive dystonia-parkinsonism (DYT3)].
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.
Kaji
Ryuji
R
Department of Clinical Neuroscience, Tokushima University.
Goto
Satoshi
S
Tamiya
Gen
G
Lee
L V
LV
D003342:Corpus Striatum / Q000473:pathology; D004298:Dopamine / Q000502:physiology; D004421:Dystonia / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051548:Histone Acetyltransferases; D006801:Humans; D020734:Parkinsonian Disorders / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D017448:Receptors, Dopamine D2 / Q000235:genetics; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics; D035362:Transcription Factor TFIID / Q000235:genetics
D017448:Receptors, Dopamine D2; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D051548:Histone Acetyltransferases; C069001:TATA-binding protein associated factor 250 kDa; D004298:Dopamine