Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons

Samuel S. Pappas, Katherine Darr, Sandra M. Holley, Carlos Cepeda, Omar S. Mabrouk, Jenny Marie T. Wong, Tessa M. LeWitt, Reema Paudel, Henry Houlden, Robert T. Kennedy, Michael S. Levine, William T. Dauer

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

Striatal dysfunction plays an important role in dystonia, but the striatal cell types that contribute to abnormal movements are poorly defined. We demonstrate that conditional deletion of the DYT1 dystonia protein torsinA in embryonic progenitors of forebrain cholinergic and GABAergic neurons causes dystonic-like twisting movements that emerge during juvenile CNS maturation. The onset of these movements coincides with selective degeneration of dorsal striatal large cholinergic interneurons (LCI), and surviving LCI exhibit morphological, electrophysiological, and connectivity abnormalities. Consistent with the importance of this LCI pathology, murine dystoniclike movements are reduced significantly with an antimuscarinic agent used clinically, and we identify cholinergic abnormalities in postmortem striatal tissue from DYT1 dystonia patients. These findings demonstrate that dorsal LCI have a unique requirement for torsinA function during striatal maturation, and link abnormalities of these cells to dystonic-like movements in an overtly symptomatic animal model.

Original languageEnglish (US)
Article numbere08352
Pages (from-to)1-25
Number of pages25
JournaleLife
Volume4
Issue numberJUNE
DOIs
StatePublished - Jun 8 2015
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Pappas, S. S., Darr, K., Holley, S. M., Cepeda, C., Mabrouk, O. S., Wong, J. M. T., LeWitt, T. M., Paudel, R., Houlden, H., Kennedy, R. T., Levine, M. S., & Dauer, W. T. (2015). Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons. eLife, 4(JUNE), 1-25. [e08352]. https://doi.org/10.7554/eLife.08352