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

• Published in: bioRxiv
• Main Authors: D'ignazio, Laura, Jacomini, Ricardo S, Qamar, Bareera, Kynon Jm Benjamin, Arora, Ria, Sawada, Tomoyo, Evans, Taylor A, Diffenerfer, Kenneth E, Pankonin, Aimee R, Hendriks, William T, Hyde, Thomas M, Kleinman, Joel E, Weinberger, Daniel, Bragg, D Cristopher, Apua Cm Paquola, Erwin, Jennifer A
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 27.03.2022
• Subjects: Age; Autopsy; Basal ganglia; Brain; Brain stem; Caudate nucleus; Central nervous system diseases; Dystonia; Females; Haplotypes; Movement disorders; Neostriatum; Neurodegeneration; Ontogeny; Pluripotency; Stem cells; Synergism; TFIID protein; Transcription initiation
• DOI: 10.1101/2022.03.26.485862

X-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 age of onset are unknown. Developing therapeutics that target XDP-related mechanisms requires a deeper understanding of how XDP-relevant features vary in health and disease. XDP is due, in part, to either a partial loss of TAF1 function and/or a SVA-driven pathological gain of function. A disease-specific SINE-VNTR-Alu (SVA) retrotransposon insertion occurs within intron 32 of TAF1, 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 XDP female carrier individuals, and identified isogenic lines where one clonal iPSC line expressed the wild-type X, and the two other clonal iPSC lines expressed the XDP haplotype. Furthermore, we characterized XDP-relevant transcript expression variation in humans, and found that SVA-F expression decreases slightly after 30 years of age in the neurotypical human brain and that TAF1 is modestly decreased in the majority of female samples. Uniquely in the caudate nucleus, TAF1 expression is not sexually dymorphic and decreased after 15 years of age. These findings indicate that regional-, age- and sex-specific mechanisms regulate TAF1, highlighting the importance of disease-relevant models and postmortem tissue analysis. We propose that the decreased TAF1 expression in the adult caudate may synergize with the XDP-specific partial loss of TAF1 function in patients, thereby passing a minimum threshold of TAF1 function, and triggering degeneration in the neostriatum. Competing Interest Statement The authors have declared no competing interest.