Genome editing in induced pluripotent stem cells rescues TAF1 levels in X-linked dystonia-parkinsonism

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: (1) TAF1 reduction in X‐linked dystonia‐parkinsonism is likely due to the retrotransposon insertion and is recapitulated in induced pluripotent stem cells and differentiated spiny projection neurons. (2) TAF1 reduction is a tractable molecular phenotype of X‐linked dystonia‐parkinsonism that can be driven by excision of the retrotransposon insertion. (3) Successful rescue of the molecular phenotype in an endogenous, genome‐edited model serves as a proof of principle that may successfully be transferred to other inherited neurodegenerative diseases.