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

Laura D’ignazio, Ricardo S. Jacomini, Bareera Qamar, Kynon J.M. Benjamin, Ria Arora, Tomoyo Sawada, Taylor A. Evans, Kenneth E. Diffenderfer, Aimee R. Pankonin, William T. Hendriks, Thomas M. Hyde, Joel E. Kleinman, Daniel R. Weinberger, D. Cristopher Bragg, Apua C.M. Paquola, Jennifer A. Erwin

Research output: Contribution to journalArticlepeer-review

Abstract

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 in-tron 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.

Original languageEnglish (US)
Article numberENEURO.0129-22.2022
JournaleNeuro
Volume9
Issue number4
DOIs
StatePublished - Jul 1 2022

Keywords

  • SVA ret-rotransposon
  • X-linked dystonia parkinsonism
  • induced pluripotent stem cells
  • movement disorder
  • neurodegeneration
  • repeat expansion

ASJC Scopus subject areas

  • General Neuroscience

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