Molecular dissection and anatomical basis 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. 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, Institute of Health Biosciences, The University of Tokushima,Graduate School, Japan.
Goto
Satoshi
S
Tamiya
Gen
G
Ando
Satoshi
S
Makino
Satoshi
S
Lee
L V
LV
D041321:Chromosomes, Human, X; D003342:Corpus Striatum / Q000473:pathology; D004421:Dystonia / Q000235:genetics* / Q000473:pathology*; D005808:Genes, Recessive; D040181:Genetic Diseases, X-Linked / Q000473:pathology*; D051548:Histone Acetyltransferases; D006801:Humans; D008954:Models, Biological; D009474:Neurons / Q000473:pathology; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000473:pathology; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics*; D035362:Transcription Factor TFIID / Q000235:genetics*
D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D051548:Histone Acetyltransferases; C069001:TATA-binding protein associated factor 250 kDa