RNA-binding protein TLS is a major nuclear aggregate-interacting protein in Huntingtin exon 1 with expanded polyglutamine-expressing cells

Hiroshi Doi, Kazumasa Okamura, Peter O. Bauer, Yoshiaki Furukawa, Hideaki Shimizu, Masaru Kurosawa, Yoko Machida, Haruko Miyazaki, Kenichi Mitsui, Yoshiyuki Kuroiwa, Nobuyuki Nukina

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Abstract

Formation of intracellular aggregates is the hallmark of polyglutamine (polyQ) diseases. We analyzed the components of purified nuclear polyQ aggregates by mass spectrometry. As a result, we found that the RNA-binding protein translocated in liposarcoma (TLS) was one of the major components of nuclear polyQ aggregate-interacting proteins in a Huntington disease cell model and was also associated with neuronal intranuclear inclusions of R6/2 mice. In vitro study revealed that TLS could directly bind to truncated N-terminal huntingtin (tNhtt) aggregates but could not bind to monomer GST-tNhtt with 18, 42, or 62Q, indicating that the tNhtt protein acquired the ability to sequester TLS after forming aggregates. Thioflavin T assay and electron microscopic study further supported the idea that TLS bound to tNhtt-42Q aggregates at the early stage of tNhtt-42Q amyloid formation. Immunohistochemistry showed that TLS was associated with neuronal intranuclear inclusions of Huntington disease human brain. Because TLS has a variety of functional roles, the sequestration of TLS to polyQ aggregates may play a role in diverse pathological changes in the brains of patients with polyQ diseases.

Original languageEnglish
Pages (from-to)6489-6500
Number of pages12
JournalJournal of Biological Chemistry
Volume283
Issue number10
DOIs
Publication statusPublished - 2008 Mar 7

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Doi, H., Okamura, K., Bauer, P. O., Furukawa, Y., Shimizu, H., Kurosawa, M., Machida, Y., Miyazaki, H., Mitsui, K., Kuroiwa, Y., & Nukina, N. (2008). RNA-binding protein TLS is a major nuclear aggregate-interacting protein in Huntingtin exon 1 with expanded polyglutamine-expressing cells. Journal of Biological Chemistry, 283(10), 6489-6500. https://doi.org/10.1074/jbc.M705306200