Identification and localization of a neuron-specific isoform of TAF1 in rat brain: implications for neuropathology of DYT3 dystonia

Sako, Wataru; Morigaki, Ryoma; Kaji, Ryuji; Tooyama, Ikuo; Okita, Shinya; Kitazato, Keiko T.; Saijo, Nagahiro; Graybiel, Ann M.; Goto, Satoshi

doi:10.1016/j.neuroscience.2011.05.031

Cited by 32 publications

(26 citation statements)

References 34 publications

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“…These results support previous findings that TAF1 is nuclear DNA-binding protein. We have reported the immunohistochemical staining of N-TAF1 in the rat striatum using 3F-11 [15]. This study confirms the data and further demonstrates immunocytochemistry of cultured cells and immunoprecitation assay using 3A-11F, as compared with polyclonal antibody to TAF1.…”

Section: Resultssupporting

confidence: 86%

Generation of a Monoclonal Antibody Specifically Reacting with Neuron-specific TATA-Box Binding Protein-Associated Factor 1 (N-TAF1)

et al. 2012

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TATA-box binding protein-associated factor 1 (TAF1), the largest subunit of the transcription factor IID complex, plays an important role in the RNA polymerase IImediated gene transcription pathway regulating the transcription of a large number of genes related to cell division. The neuron-specific isoform of the TAF1 gene (N-TAF1) may have an essential role in neurons through transcriptional regulation of many neuron-specific genes. The present study reports the preparation and properties of a monoclonal antibody directed against N-TAF1. The monoclonal antibody, 3A-11F, specifically recognized N-TAF1 protein with no reactivity to TAF1 protein, as evidenced by immunocytochemistry and immunoprecipitation using cultured cells expressing recombinant N-TAF1 or TAF1 protein. Immunohistochemistry using 3A-11F showed that N-TAF1-imunoreactivity was detected in the nuclear region of neurons in the rat brain. The 3A-11F monoclonal antibody promises to be a useful tool for determining the expression pattern and biological function of N-TAF1 in the brain.

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Section: Resultssupporting

confidence: 86%

Generation of a Monoclonal Antibody Specifically Reacting with Neuron-specific TATA-Box Binding Protein-Associated Factor 1 (N-TAF1)

et al. 2012

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“…Of note, a similar situation exists in DYT3, in which a neuronal specific isoform of the causative protein, TAF1, was identified [27,28]. This novel Thap1 species was most abundant in cerebellum where its levels were obviously developmentally regulated.…”

Section: Discussionmentioning

confidence: 77%

Dystonia type 6 gene product Thap1: identification of a 50 kDa DNA-binding species in neuronal nuclear fractions

Ortiz-Virumbrales

Ruiz

Hone

et al. 2014

acta neuropathol commun

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Mutations in THAP1 result in dystonia type 6, with partial penetrance and variable phenotype. The goal of this study was to examine the nature and expression pattern of the protein product(s) of the Thap1 transcription factor (DYT6 gene) in mouse neurons, and to study the regional and developmental distribution, and subcellular localization of Thap1 protein. The goal was accomplished via overexpression and knock-down of Thap1 in the HEK293T cell line and in mouse striatal primary cultures and western blotting of embryonic Thap1-null tissue. The endogenous and transduced Thap1 isoforms were characterized using three different commercially available anti-Thap1 antibodies and validated by immunoprecipitation and DNA oligonucleotide affinity chromatography. We identified multiple, novel Thap1 species of apparent Mr 32 kDa, 47 kDa, and 50–52 kDa in vitro and in vivo, and verified the previously identified species at 29–30 kDa in neurons. The Thap1 species at the 50 kDa size range was exclusively detected in murine brain and testes and were located in the nuclear compartment. Thus, in addition to the predicted 25 kDa apparent Mr, we identified Thap1 species with greater apparent Mr that we speculate may be a result of posttranslational modifications. The neural localization of the 50 kDa species and its nuclear compartmentalization suggests that these may be key Thap1 species controlling neuronal gene transcription. Dysfunction of the neuronal 50 kDa species may therefore be implicated in the pathogenesis of DYT6.

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“…7,8 None of these diseaseassociated genetic variants are located in protein-coding segments based on current annotations of the human genome, although the regulation of neuron-specific TAF1 isoforms or of other genes in the region has been postulated as disease mechanisms. [7][8][9] Nevertheless, the exact disease-causing variant has been a matter of debate, [9][10][11][12] and theoretically, only one-if any-is functionally related to disease causation, whereas the remaining are merely benign variants.…”

Section: Introductionmentioning

confidence: 99%

New insights into the genetics of X-linked dystonia-parkinsonism (XDP, DYT3)

Domingo

Westenberger

Lee³

et al. 2015

Eur J Hum Genet

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X-linked recessive dystonia-parkinsonism is a rare movement disorder that is highly prevalent in Panay Island in the Philippines. Earlier studies identified seven different genetic alterations within a 427-kb disease locus on the X chromosome; however, the exact disease-causing variant among these is still not unequivocally determined. To further investigate the genetic cause of this disease, we sequenced all previously reported genetic alterations in 166 patients and 473 Filipino controls. Singly occurring variants in our ethnically matched controls would have allowed us to define these as polymorphisms, but none were found. Instead, we identified five patients carrying none of the disease-associated variants, and one male control carrying all of them. In parallel, we searched for novel single-nucleotide variants using next-generation sequencing. We did not identify any shared variants in coding regions of the X chromosome. However, by validating intergenic variants discovered via genome sequencing, we were able to define the boundaries of the disease-specific haplotype and narrow the disease locus to a 294-kb region that includes four known genes. Using microarray-based analyses, we ruled out the presence of disease-linked copy number variants within the implicated region. Finally, we utilized in silico analysis and detected no strong evidence of regulatory regions surrounding the disease-associated variants. In conclusion, our finding of disease-specific variants occurring in complete linkage disequilibrium raises new insights and intriguing questions about the origin of the disease haplotype, the existence of phenocopies and of reduced penetrance, and the causative genetic alteration in XDP.

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Identification and localization of a neuron-specific isoform of TAF1 in rat brain: implications for neuropathology of DYT3 dystonia

Cited by 32 publications

References 34 publications

Generation of a Monoclonal Antibody Specifically Reacting with Neuron-specific TATA-Box Binding Protein-Associated Factor 1 (N-TAF1)

Generation of a Monoclonal Antibody Specifically Reacting with Neuron-specific TATA-Box Binding Protein-Associated Factor 1 (N-TAF1)

Dystonia type 6 gene product Thap1: identification of a 50 kDa DNA-binding species in neuronal nuclear fractions

New insights into the genetics of X-linked dystonia-parkinsonism (XDP, DYT3)

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