Abstract | BACKGROUND: The most likely genetic cause of X-linked dystonia-parkinsonism, a neurodegenerative movement disorder endemic to the Philippines, is a 2672-bp-long retrotransposon insertion in intron 32 of the TAF1 gene. The objectives of this study were to investigate whether (1) TAF1 expression is altered in induced pluripotent stem cells and differentiated neuronal models and (2) excision of the retrotransposon insertion restores normal TAF1 expression. METHODS: Expression of TAF1 and its neuronal isoform were determined in induced pluripotent stem cells and in induced pluripotent stem cell-derived cortical neurons and spiny projection neurons using quantitative PCR. Genome editing-based excision of the retrotransposon insertion was performed on induced pluripotent stem cells from 3 X-linked dystonia-parkinsonism patients. Edited and unedited induced pluripotent stem cells from X-linked dystonia-parkinsonism patients and controls were differentiated into cortical neurons and spiny projection neurons, and TAF1 expression was compared across groups. RESULTS: TAF1 was reduced in patient-derived induced pluripotent stem cells (P < 0.05) and spiny projection neurons (P < 0.01). After genome editing, we observed higher TAF1 expression in edited compared with unedited induced pluripotent stem cells (P < 0.0001). In edited spiny projection neurons, TAF1 expression was also increased, but did not reach statistical significance. No expression differences were observed in cortical neurons. CONCLUSIONS:
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Authors | Aleksandar Rakovic, Aloysius Domingo, Karen Grütz, Leonora Kulikovskaja, Philipp Capetian, Sally A Cowley, Insa Lenz, Norbert Brüggemann, Raymond Rosales, Dominic Jamora, Arndt Rolfs, Philip Seibler, Ana Westenberger, Inke König, Christine Klein |
Journal | Movement disorders : official journal of the Movement Disorder Society
(Mov Disord)
Vol. 33
Issue 7
Pg. 1108-1118
(07 2018)
ISSN: 1531-8257 [Electronic] United States |
PMID | 30153385
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2018 International Parkinson and Movement Disorder Society. |
Chemical References |
- GDF3 protein, human
- Growth Differentiation Factor 3
- Nanog Homeobox Protein
- Nerve Tissue Proteins
- Octamer Transcription Factor-3
- POU5F1 protein, human
- RNA, Messenger
- SOX2 protein, human
- SOXB1 Transcription Factors
- TATA-Binding Protein Associated Factors
- TUBB3 protein, human
- Transcription Factor TFIID
- Tubulin
- Histone Acetyltransferases
- TATA-binding protein associated factor 250 kDa
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Topics |
- Adult
- Cells, Cultured
- Cerebral Cortex
(cytology)
- Dystonic Disorders
(genetics, metabolism)
- Female
- Gene Editing
(methods)
- Genetic Diseases, X-Linked
(genetics, metabolism)
- Growth Differentiation Factor 3
(metabolism)
- Histone Acetyltransferases
(metabolism)
- Humans
- Induced Pluripotent Stem Cells
(physiology)
- Male
- Middle Aged
- Nanog Homeobox Protein
(metabolism)
- Nerve Tissue Proteins
(metabolism)
- Octamer Transcription Factor-3
(metabolism)
- RNA, Messenger
(metabolism)
- SOXB1 Transcription Factors
(genetics, metabolism)
- TATA-Binding Protein Associated Factors
(metabolism)
- Transcription Factor TFIID
(metabolism)
- Transfection
- Tubulin
(metabolism)
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