Variation in TAF1 Expression in Female Carrier-Induced Pluripotent Stem Cells and Human Brain Ontogeny Has Implications for Adult Neostriatum Vulnerability in X-Linked Dystonia Parkinsonism

Abstract

AbstractX-linked dystonia-parkinsonism (XDP) is an inherited, X-linked, adult-onset movement disorder characterized by degeneration in the neostriatum. No therapeutics alter disease progression. The mechanisms underlying regional differences in degeneration and adult onset are unknown. Developing therapeutics requires a deeper understanding of how XDP-relevant features vary in health and disease. XDP is possibly due, in part, to a partial loss ofTAF1function. A disease-specific SINE-VNTR-Alu (SVA) retrotransposon insertion occurs within intron 32 ofTAF1, a subunit of TFIID involved in transcription initiation. While all XDP males are usually clinically affected, females are heterozygous carriers generally not manifesting the full syndrome. As a resource for disease modeling, we characterized eight iPSC lines from three XDP female carrier individuals for X chromosome inactivation (XCI) status and identified clonal lines that express either the wild-type X or XDP haplotype. Furthermore, we characterized XDP-relevant transcript expression in neurotypical humans, and found that SVA-F expression decreases after 30 years of age in the brain and thatTAF1is decreased in most female samples. Uniquely in the caudate nucleus,TAF1expression is not sexually dimorphic and decreased after adolescence. These findings indicate that regional-specific, age-specific, and sex-specific mechanisms regulateTAF1, highlighting the importance of disease-relevant models and postmortem tissue. We propose that the decreasedTAF1expression in the adult caudate may synergize with the XDP-specific partial loss ofTAF1function in patients, thereby passing a minimum threshold ofTAF1function, and triggering degeneration in the neostriatum.