Mitochondrial toxins cause widespread downregulation of pathways in X-linked dystonia-parkinsonism patient-derived neurons.
Karen Grütz, Axel Künstner, Christin Krause, Letizia Santinelli, Sören Franzenburg, Jenny Ghelfi, Anne Grünewald, Raymond L Rosales, Norbert Brüggemann, Hauke Busch, Christine Klein, Philip Seibler
Abstract
The genetic mechanism underlying the neurodegenerative movement disorder X-linked dystonia-parkinsonism (XDP) involves a retrotransposon insertion within the TAF1 gene. TAF1 encodes the TATA-box binding protein-associated factor 1, the largest subunit of the basal transcription factor TFIID, which connects transcription activation to the assembly of the RNA polymerase II preinitiation complex at the core promoter of genes. This study investigated how the TAF1 mutation affects the transcriptomes of XDP patient-derived neurons under basal conditions and in response to mitochondrial toxins. Gene set enrichment analysis revealed that, under basal conditions, patient-derived neurons exhibited predominantly upregulated pathways compared to controls. However, exposure to mitochondrial toxins induced a global shift toward downregulation of pathways in XDP neurons, affecting genome maintenance, epigenetic regulation, adaptive neuronal function, and transcription. Our findings suggest that neurons from XDP patients are more susceptible to mitochondrial stress than controls, leading to widespread transcriptomic downregulation and increased DNA damage.