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.
| Title: | 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. |
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| Authors: | D'Ignazio L; Lieber Institute for Brain Development, Baltimore, MD 21205.; Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.; Jacomini RS; Lieber Institute for Brain Development, Baltimore, MD 21205.; Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.; Qamar B; Lieber Institute for Brain Development, Baltimore, MD 21205.; Benjamin KJM; Lieber Institute for Brain Development, Baltimore, MD 21205.; Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.; Department of Psychiatry & Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.; Arora R; Lieber Institute for Brain Development, Baltimore, MD 21205.; Department of Biology, Krieger School of Arts & Sciences, Johns Hopkins University, Baltimore, MD 21218.; Sawada T; Lieber Institute for Brain Development, Baltimore, MD 21205.; Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.; Evans TA; Lieber Institute for Brain Development, Baltimore, MD 21205.; Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.; Diffenderfer KE; Stem Cell Core, Salk Institute for Biological Studies, La Jolla, CA 92037.; Pankonin AR; Stem Cell Core, Salk Institute for Biological Studies, La Jolla, CA 92037.; Hendriks WT; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129.; Hyde TM; Lieber Institute for Brain Development, Baltimore, MD 21205.; Department of Psychiatry & Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.; Kleinman JE; Lieber Institute for Brain Development, Baltimore, MD 21205.; Department of Psychiatry & Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.; Weinberger DR; Lieber Institute for Brain Development, Baltimore, MD 21205.; Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.; Department of Psychiatry & Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.; McKusick-Nathans Department of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.; Bragg DC; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129.; Paquola ACM; Lieber Institute for Brain Development, Baltimore, MD 21205.; Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.; Erwin JA; Lieber Institute for Brain Development, Baltimore, MD 21205 jennifer.erwin@libd.org.; Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.; Department of Psychiatry & Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD 21205. |
| Source: | ENeuro [eNeuro] 2022 Aug 30; Vol. 9 (4). Date of Electronic Publication: 2022 Aug 30 (Print Publication: 2022). |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Society for Neuroscience Country of Publication: United States NLM ID: 101647362 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 2373-2822 (Electronic) Linking ISSN: 23732822 NLM ISO Abbreviation: eNeuro Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Washington, DC] : Society for Neuroscience, [2014]- |
| MeSH Terms: | Transcription Factor TFIID*/metabolism ; Transcription Factor TFIID*/genetics ; TATA-Binding Protein Associated Factors*/metabolism ; TATA-Binding Protein Associated Factors*/genetics ; Genetic Diseases, X-Linked*/metabolism ; Genetic Diseases, X-Linked*/genetics ; Genetic Diseases, X-Linked*/pathology ; Dystonic Disorders*/genetics ; Dystonic Disorders*/metabolism ; Dystonic Disorders*/pathology ; Induced Pluripotent Stem Cells*/metabolism ; Histone Acetyltransferases*/metabolism ; Histone Acetyltransferases*/genetics ; Brain*/metabolism ; Brain*/growth & development; Humans ; Female ; Adult ; Male ; Heterozygote ; X Chromosome Inactivation |
| 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 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.; (Copyright © 2022 D’Ignazio et al.) |
| Grant Information: | T32 MH015330 United States MH NIMH NIH HHS |
| Contributed Indexing: | Keywords: SVA retrotransposon; X-linked dystonia parkinsonism; induced pluripotent stem cells; movement disorder; neurodegeneration; repeat expansion |
| Substance Nomenclature: | 0 (Transcription Factor TFIID); 0 (TATA-Binding Protein Associated Factors); EC 2.7.11.1 (TATA-binding protein associated factor 250 kDa); EC 2.3.1.48 (Histone Acetyltransferases) |
| SCR Disease Name: | Dystonia 3, Torsion, X-Linked |
| Entry Date(s): | Date Created: 20220722 Date Completed: 20260512 Latest Revision: 20260512 |
| Update Code: | 20260512 |
| PubMed Central ID: | PMC9428949 |
| DOI: | 10.1523/ENEURO.0129-22.2022 |
| PMID: | 35868859 |
| Database: | MEDLINE |
Journal Article