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Understanding the Role of Thap1 in the Nervous System: Linking Transcriptional Deficits to Pathological Alterations in Dystonia

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Dystonia is a movement disorder characterized by involuntary and repetitive co-contractions of the agonist and antagonist muscles. Dystonia 6 (DYT6) is an autosomal dominant dystonia caused by loss of function mutations in the zinc finger transcription factor THAP1. I have generated Thap1 knock-out mice with a view to understanding its transcriptional role. While germ-line deletion of Thap1 is embryonic lethal, mice lacking one Thap1 allele—which in principle should recapitulate the haploinsufficiency of the human syndrome—do not show a discernable phenotype. This is because mice show autoregulation of Thap1 mRNA levels with upregulation at the non-affected locus. I then deleted Thap1 in glial and neuronal precursors using a nestin-conditional approach. Although these mice do not exhibit dystonia, they show pronounced locomotor deficits reflecting derangements in the cerebellar and basal ganglia circuitry, the circuits postulated to be most affected in dystonia. These behavioral features are associated with alterations in the expression of genes involved in nervous system development, synaptic transmission, cytoskeleton, gliosis, and dopamine signaling that link DYT6 to other isolated and combined dystonic syndromes. The altered gene networks underlie the observed multicellular pathology: abnormal neuronal morphology, decreased spine density, decreased myelination, increased gliosis, and altered dopaminergic function, which consistent with other dystonia models and human patients.

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