TY - JOUR T1 - 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 JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0129-22.2022 VL - 9 IS - 4 SP - ENEURO.0129-22.2022 AU - Laura D’Ignazio AU - Ricardo S. Jacomini AU - Bareera Qamar AU - Kynon J. M. Benjamin AU - Ria Arora AU - Tomoyo Sawada AU - Taylor A. Evans AU - Kenneth E. Diffenderfer AU - Aimee R. Pankonin AU - William T. Hendriks AU - Thomas M. Hyde AU - Joel E. Kleinman AU - Daniel R. Weinberger AU - D. Cristopher Bragg AU - Apua C. M. Paquola AU - Jennifer A. Erwin Y1 - 2022/07/01 UR - http://www.eneuro.org/content/9/4/ENEURO.0129-22.2022.abstract N2 - 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 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 of TAF1 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 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 that TAF1 is decreased in most female samples. Uniquely in the caudate nucleus, TAF1 expression is not sexually dimorphic and decreased after adolescence. These findings indicate that regional-specific, age-specific, and sex-specific mechanisms regulate TAF1, highlighting the importance of disease-relevant models and postmortem tissue. 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. ER -