Objective: We pursue to identify dysregulated cellular pathways underlying X-linked dystonia-parkinsonism (XDP) by transcriptome profiling of induced pluripotent stem cell (iPSC)-derived neuronal cultures from XDP patients and healthy controls under basal conditions and upon treatment with cellular stressors.

Background: The molecular dysfunction in XDP, a rare neurodegenerative movement disorder endemic to the Philippines, is not entirely understood. The cause of XDP is an intronic retrotransposon insertion in the TAF1 (TATA-box binding protein-associated factor 1) gene [1]. TAF1 is the largest subunit of the transcription factor IID complex, which is comprised of the TATA-binding protein (TBP) and 13 different TAFs. It plays an important role in the RNA polymerase II-mediated gene transcription pathway.

Method: We differentiated iPSCs into cortical neurons and performed bulk RNA-seq analysis in six patient and six control samples cultured under basal conditions as well as three patient and six control samples treated with mitochondrial toxins that have been implicated in experimental models for Parkinson’s disease.

Results: Transcriptome profiling revealed differentially expressed genes (q < 0.05) for both treated (82 genes) and untreated (124 genes) conditions. Most importantly, gene set enrichment analysis against REACTOME gene sets indicated that upon treatment with mitochondrial toxins, the RNA Polymerase I Promoter Opening and the RNA Polymerase I Transcription pathways were significantly downregulated in patient neurons compared to controls (q < 0.05).

Polymerase I transcription requires the upstream binding factor UBF. Notably, an interaction between UBF and TAF1 has been identified, in which TAF1 stimulates ribosomal DNA transcription in a dosage-dependent manner by binding to the activator UBF [2].

Conclusion: Key cellular pathways relating to promotor opening and transcription were downregulated in iPSC-derived neuronal cells of XDP patients suggesting that stress-related impaired RNA polymerase I transcription might contribute to the pathogenesis of XDP.

References: [1] Aneichyk T, Hendriks WT, Yadav R, et al. Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly. Cell. 2018;172:897-909.e21.

[2] Lin CY, Tuan J, Scalia P, et al. The cell cycle regulatory factor TAF1 stimulates ribosomal DNA transcription by binding to the activator UBF. Curr Biol. 2002;12:2142-6.

« Back to 2023 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/transcriptional-dysregulation-in-ipsc-derived-neurons-from-patients-with-x-linked-dystonia-parkinsonism/